[Paper-level Aggregated] PMCID: PMC9468105

Evidence Type(s): Predisposing

Summary: Mutation: p.R1276 | Summary: The p.R1276 mutation is described as a germline mutation associated with an autosomal dominant tumor predisposition syndrome, indicating it confers inherited risk for disease.

Evidence Type: Predisposing

Gene→Variant (gene-first): NF1(4763):p.R1276*

Genes: NF1(4763)

Variants: p.R1276*

[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predisposing, Oncogenic

Summary: Evidence Type: Predisposing | Mutation: p.R1276 | Summary: The p.R1276 mutation is described as a germline mutation associated with an autosomal dominant tumor predisposition syndrome, indicating it confers inherited risk for disease. Evidence Type: Oncogenic | Mutation: c.4110 + 2 T > G | Summary: The c.4110 + 2 T > G splice site mutation contributes to the somatic inactivation of the remaining wild-type NF1 allele, indicating its role in tumor development.

Gene→Variant (gene-first): 4763:c.4110 + 2 T > G 4763:p.R1276*

Genes: 4763

Variants: c.4110 + 2 T > G p.R1276*

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Predisposing

Summary: Mutation: c.236A>G; p.Tyr79Cys | Summary: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease, indicating it may confer inherited risk for the disease.

Gene→Variant (gene-first): HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys

Genes: HIF1A(3091)

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: c.236A>G; p.Tyr79Cys | Summary: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease, indicating it may confer inherited risk for the disease. Evidence Type: Oncogenic | Mutation: c.236A>G; p.Tyr79Cys | Summary: The p.Tyr79Cys substitution is noted as a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC), suggesting it contributes to tumor development or progression. Evidence Type: Functional | Mutation: c.236A>G; p.Tyr79Cys | Summary: The variant has been shown to mimic the effects of pVHL deficiency on hypoxic signaling, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paper-level Aggregated] PMCID: PMC7785563

Evidence Type(s): Predisposing

Summary: Mutation: MSH2 (germline) | Summary: The presence of a known deleterious germline MSH2 mutation in cases diagnosed with Lynch syndrome suggests an inherited risk for colorectal cancer.

Evidence Type: Predisposing Mutation: MSH6 (germline) | Summary: The identification of germline mutations in MSH6 in several tumors indicates a hereditary predisposition to MMR-deficiency syndromes, including Lynch syndrome.

Gene→Variant (gene-first): NA:MSH2 (germline) NA:MSH6 (germline)

Genes: NA

Variants: MSH2 (germline) MSH6 (germline)

[Paragraph-level] PMCID: PMC7785563 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Predisposing, Functional

Summary: Evidence Type: Oncogenic | Mutation: R132H | Summary: The IDH1-R132H mutation is associated with conventional supratentorial IDH-mutant astrocytomas, indicating its role in tumor development or progression. Evidence Type: Predisposing | Mutation: MSH2 (germline) | Summary: The presence of a known deleterious germline MSH2 mutation in cases diagnosed with Lynch syndrome suggests an inherited risk for colorectal cancer. Evidence Type: Predisposing | Mutation: MSH6 (germline) | Summary: The identification of germline mutations in MSH6 in several tumors indicates a hereditary predisposition to MMR-deficiency syndromes, including Lynch syndrome. Evidence Type: Functional | Mutation: MSH6 | Summary: The tumor cell-specific loss of MSH6 expression in one case suggests that the mutation alters the molecular function of the MMR pathway, contributing to tumorigenesis.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paper-level Aggregated] PMCID: PMC7342819

Evidence Type(s): Predisposing

Summary: Mutation: c.3114-1G>A | Summary: The PALB2 c.3114-1G>A mutation is described as a germline mutation detected in peripheral blood cells, indicating an inherited risk for disease and a predisposition to cancer in this patient.

Gene→Variant (gene-first): PALB2(79728):c.3114-1G>A

Genes: PALB2(79728)

Variants: c.3114-1G>A

[Paragraph-level] PMCID: PMC7342819 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Oncogenic, Predisposing

Summary: Evidence Type: Oncogenic | Mutation: c.2514+1G>C | Summary: The somatic mutation c.2514+1G>C in PALB2 is associated with tumor development or progression, contributing to the patient's pancreatic cancer. Evidence Type: Predisposing | Mutation: c.3114-1G>A | Summary: The germline mutation c.3114-1G>A in PALB2 is associated with an inherited risk for disease, indicating a predisposition to cancer in this patient.

Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A

Genes: 79728

Variants: c.2514+1G>C c.3114-1G>A

[Paragraph-level] PMCID: PMC7342819 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic, Predisposing

Summary: Evidence Type: Oncogenic | Mutation: p.G12V | Summary: The KRAS p.G12V mutation is identified as a common driver mutation contributing to tumor development in the context of pancreatic adenocarcinoma (PAAD). Evidence Type: Predisposing | Mutation: c.3114-1G>A | Summary: The PALB2 c.3114-1G>A mutation is described as a germline mutation detected in peripheral blood cells, indicating an inherited risk for disease. Evidence Type: Oncogenic | Mutation: c.2514+1G>C | Summary: The PALB2 c.2514+1G>C mutation is noted as a somatic mutation likely contributing to tumor progression, associated with a deficiency in DNA homologous recombination.

Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A 3845:p.G12V

Genes: 79728 3845

Variants: c.2514+1G>C c.3114-1G>A p.G12V

[Paper-level Aggregated] PMCID: PMC5111006

Evidence Type(s): Predisposing

Summary: Mutation: rs1042522 | Summary: The variant rs1042522 (TP53, p.P72R) is associated with Li-Fraumeni syndrome, indicating a potential inherited risk for disease.

Evidence Type: Predisposing Mutation: rs169547 | Summary: The variant rs169547 (BRCA2, p.V2466A) is linked to hereditary breast/ovarian cancer, suggesting it may confer inherited risk for disease.

Gene→Variant (gene-first): TP53(7157):rs1042522 BRCA2(675):rs169547

Genes: TP53(7157) BRCA2(675)

Variants: rs1042522 rs169547

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing

Summary: Evidence Type: Predisposing | Mutation: rs1042522 | Summary: The variant rs1042522 (TP53, p.P72R) is associated with Li-Fraumeni syndrome, indicating a potential inherited risk for disease. Evidence Type: Predisposing | Mutation: rs169547 | Summary: The variant rs169547 (BRCA2, p.V2466A) is linked to hereditary breast/ovarian cancer, suggesting it may confer inherited risk for disease.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Predisposing

Summary: Mutation: p.Glu726Lys | Summary: The presence of the p.Glu726Lys mutation in patients indicates a potential inherited risk for developing MCAP and its associated features.

Gene→Variant (gene-first): PIK3CA(5290):p.Glu726Lys

Genes: PIK3CA(5290)

Variants: p.Glu726Lys

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Summary: Evidence Type: Diagnostic | Mutation: p.Glu726Lys | Summary: The p.Glu726Lys mutation is associated with classic features of MCAP, which helps in defining and classifying the disease. Evidence Type: Predisposing | Mutation: p.Glu726Lys | Summary: The presence of the p.Glu726Lys mutation in patients indicates a potential inherited risk for developing MCAP and its associated features. Evidence Type: Oncogenic | Mutation: p.Glu726Lys | Summary: The p.Glu726Lys mutation in PIK3CA is implicated in tumor development and progression, contributing to the oncogenic characteristics observed in patients with MCAP.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

[Paper-level Aggregated] PMCID: PMC4845427

Evidence Type(s): Predisposing

Summary: Mutation: A to I | Summary: The RUNX1 alterations are germline, suggesting they confer inherited risk for disease in the identified pedigrees.

Gene→Variant (gene-first): RUNX1(861):A to I

Genes: RUNX1(861)

Variants: A to I

[Paragraph-level] PMCID: PMC4845427 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predisposing

Summary: Evidence Type: Predisposing | Mutation: A to I | Summary: The passage indicates that the RUNX1 alterations are germline, suggesting they confer inherited risk for disease in the identified pedigrees.

Gene→Variant (gene-first): 861:A to I

Genes: 861

Variants: A to I

[Paper-level Aggregated] PMCID: PMC4477877

Evidence Type(s): Predisposing

Summary: Mutation: p. L349P | Summary: The p. L349P mutation is identified as a germline variant associated with inherited susceptibility to acute leukemia, suggesting it confers inherited risk for the disease.

Evidence Type: Predisposing Mutation: p. N385fs | Summary: The N385fs mutation is identified as a germline mutation linked to inherited risk for acute leukemia, supporting its role as a predisposing factor.

Evidence Type: Predisposing Mutation: c.1153-5_1153_1delAACAG | Summary: The heterozygous deletion in ETV6 was identified in the proband and his mother, suggesting an inherited risk for acute lymphoblastic leukemia (ALL).

Evidence Type: Predisposing Mutation: V37M | Summary: The V37M variant is described as a rare germline variant, indicating it may confer inherited risk for leukemia.

Evidence Type: Predisposing Mutation: R181H | Summary: The R181H variant is classified as a rare germline variant, suggesting a potential inherited risk for leukemia.

Gene→Variant (gene-first): ETV6(2120):p. L349P ETV6(2120):p. N385fs ETV6(2120):c.1153-5_1153_1delAACAG ETV6(2120):V37M ETV6(2120):R181H

Genes: ETV6(2120)

Variants: p. L349P p. N385fs c.1153-5_1153_1delAACAG V37M R181H

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Predisposing

Summary: Evidence Type: Oncogenic | Mutation: V37M | Summary: The V37M variant was identified in patients with B-ALL, indicating a potential contribution to tumor development in leukemia. Evidence Type: Oncogenic | Mutation: R181H | Summary: The R181H variant was also found in patients with B-ALL, suggesting its involvement in tumor progression. Evidence Type: Predisposing | Mutation: V37M | Summary: The V37M variant is described as a rare germline variant, indicating it may confer inherited risk for leukemia. Evidence Type: Predisposing | Mutation: R181H | Summary: The R181H variant is also classified as a rare germline variant, suggesting a potential inherited risk for leukemia.

Gene→Variant (gene-first): 2120:11905459G>A 2120:12022436 G>A 2120:R181H 2120:V37M 2120:rs150089916

Genes: 2120

Variants: 11905459G>A 12022436 G>A R181H V37M rs150089916

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 6

Evidence Type(s): Predisposing, Oncogenic

Summary: Evidence Type: Predisposing | Mutation: c.1153-5_1153_1delAACAG | Summary: The heterozygous deletion in ETV6 was identified in the proband and his mother, suggesting an inherited risk for acute lymphoblastic leukemia (ALL). Evidence Type: Oncogenic | Mutation: N385fs | Summary: The frameshift mutation at codon 385 in ETV6 is predicted to contribute to tumor development in the context of acute lymphoblastic leukemia (ALL).

Gene→Variant (gene-first): 2120:N385fs 2120:c.1153-5_1153_1delAACAG

Genes: 2120

Variants: N385fs c.1153-5_1153_1delAACAG

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predisposing, Functional

Summary: Evidence Type: Predisposing | Mutation: L349P | Summary: The L349P mutation is described as a germline mutation associated with inherited susceptibility to acute leukemia, indicating a predisposing factor for the disease. Evidence Type: Predisposing | Mutation: N385fs | Summary: The N385fs mutation is also identified as a germline mutation linked to inherited risk for acute leukemia, supporting its role as a predisposing factor. Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation alters the localization of the ETV6 protein, preventing it from localizing to the nucleus and affecting its regulatory function. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation results in an abnormally truncated ETV6 protein, which shows decreased ability to regulate the expression of genes typically suppressed by ETV6, indicating a functional alteration.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: p. L349P | Summary: The p. L349P mutation is identified as a germline variant in a kindred affected by thrombocytopenia and acute lymphoblastic leukemia (ALL), suggesting it confers inherited risk for the disease. Evidence Type: Oncogenic | Mutation: p. N385fs | Summary: The p. N385fs mutation was found in leukemic cells, contributing to tumor development as it is associated with acute lymphoblastic leukemia (ALL) and secondary myelodysplasia/acute myeloid leukemia. Evidence Type: Functional | Mutation: p. N385fs | Summary: The p. N385fs mutation alters the molecular function of ETV6, as it impairs nuclear localization and reduces the ability to regulate the transcription of ETV6 target genes.

Gene→Variant (gene-first): 2120:p. L349P 2120:p. N385fs

Genes: 2120

Variants: p. L349P p. N385fs

[Paper-level Aggregated] PMCID: PMC4411002

Evidence Type(s): Predisposing

Summary: Mutation: c.241 G>A; p.E81K | Summary: The presence of the c.241 G>A [p.E81K] mutation in the proband's tissues, along with its absence in the blood and parents, suggests it may confer inherited risk for disease, indicating a possible germline component.

Gene→Variant (gene-first): PIK3CA(5290):c.241 G>A PIK3CA(5290):p.E81K

Genes: PIK3CA(5290)

Variants: c.241 G>A p.E81K

[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Predisposing

Summary: Evidence Type: Oncogenic | Mutation: c.241 G>A; p.E81K | Summary: The mutation c.241 G>A [p.E81K] in PIK3CA is identified as a somatic variant contributing to tumor development or progression, as it was detected in various tissues of the proband but not in the blood or parents, indicating its potential role in cancer. Evidence Type: Predisposing | Mutation: c.241 G>A; p.E81K | Summary: The presence of the c.241 G>A [p.E81K] mutation in the proband's tissues, along with its absence in the blood and parents, suggests it may confer inherited risk for disease, indicating a possible germline component.

Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K

Genes: 5290

Variants: c.241 G>A p.E81K

[Paper-level Aggregated] PMCID: PMC4150988

Evidence Type(s): Predisposing

Summary: Mutation: p.A77S | Summary: The p.A77S mutation may represent a rare germline variant, suggesting a potential inherited risk for disease, although this is unlikely based on the absence in normal genome data.

Evidence Type: Predisposing

Gene→Variant (gene-first): RIT1(6016):p.A77S

Genes: RIT1(6016)

Variants: p.A77S

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Predisposing

Summary: Evidence Type: Oncogenic | Mutation: p.A77P | Summary: The p.A77P mutation in RIT1 is associated with tumor development as it was observed in a recurrent alteration among mutated samples. Evidence Type: Predisposing | Mutation: p.A77S | Summary: The p.A77S mutation may represent a rare germline variant, suggesting a potential inherited risk for disease, although this is unlikely based on the absence in normal genome data.

Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S

Genes: NA 6016

Variants: alanine 77 p.A77P p.A77S

[Paper-level Aggregated] PMCID: PMC3293822

Evidence Type(s): Predisposing

Summary: Mutation: K720E | Summary: The K720E mutation is implicated in a 6-fold increased risk of prostate cancer, indicating its role as a predisposing variant.

Evidence Type: Predisposing

Gene→Variant (gene-first): NCOR1(9611):K720E

Genes: NCOR1(9611)

Variants: K720E

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 29

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: K720E | Summary: The K720E mutation is implicated in a 6-fold increased risk of prostate cancer, indicating its role as a predisposing variant. Evidence Type: Oncogenic | Mutation: R726L | Summary: The R726L mutation contributes to tumor development by impairing binding interactions critical for androgen receptor function. Evidence Type: Functional | Mutation: N756 | Summary: The N756 mutation may be involved in AR dimerization, and its mutation to aspartate resulted in complete loss of function. Evidence Type: Functional | Mutation: A765T | Summary: The A765T mutation displayed compromised transactivation activity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Y763C | Summary: The Y763C mutation also displayed compromised transactivation activity, suggesting it alters molecular function. Evidence Type: Functional | Mutation: Q902 | Summary: The Q902 residue is part of an H-bonding network, and its mutation to arginine (Q902R) may disrupt this interaction, indicating a functional alteration.

Gene→Variant (gene-first): 367:A765T 9611:K720E 367:N756 367:Q902 367:Q902R 367:R726L 367:Y763C 9611:lysine 720

Genes: 367 9611

Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

[Paper-level Aggregated] PMCID: PMC3184204

Evidence Type(s): Predisposing

Summary: Mutation: c.1061C>T | Summary: The c.1061C>T mutation is identified as a heterozygous variant in the GATA2 gene that segregates with the multigenerational transmission of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating its role as a predisposition gene.

Evidence Type: Predisposing Mutation: c.1063_1065delACA | Summary: The c.1063_1065delACA mutation is reported in a family with MDS/AML, supporting its classification as a predisposing variant associated with familial forms of the disease.

Gene→Variant (gene-first): GATA2(2624):c.1061C>T GATA2(2624):c.1063_1065delACA

Genes: GATA2(2624)

Variants: c.1061C>T c.1063_1065delACA

[Paragraph-level] PMCID: PMC3184204 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Functional

Summary: Evidence Type: Predisposing | Mutation: c.1061C>T | Summary: The c.1061C>T mutation is identified as a heterozygous variant in the GATA2 gene that segregates with the multigenerational transmission of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating its role as a predisposition gene. Evidence Type: Predisposing | Mutation: c.1063_1065delACA | Summary: The c.1063_1065delACA mutation is reported in a family with MDS/AML, supporting its classification as a predisposing variant associated with familial forms of the disease. Evidence Type: Functional | Mutation: c.1061C>T | Summary: The c.1061C>T mutation alters the molecular function of the GATA2 transcription factor, affecting transactivation of target genes, cellular differentiation, apoptosis, and global gene expression. Evidence Type: Functional | Mutation: c.1063_1065delACA | Summary: The c.1063_1065delACA mutation also impacts the molecular function of GATA2, influencing its role in transactivation and other cellular processes.

Gene→Variant (gene-first): 2624:c.1061C>T 2624:c.1063_1065delACA 2624:p.Thr354Met 6688:p.Thr355del

Genes: 2624 6688

Variants: c.1061C>T c.1063_1065delACA p.Thr354Met p.Thr355del

[Paper-level Aggregated] PMCID: PMC2670982

Evidence Type(s): Predisposing

Summary: Mutation: R849W | Summary: The R849W mutation is described as an inherited variant associated with a rare form of venous anomalies, indicating it confers inherited risk for disease.

Evidence Type: Predisposing

Gene→Variant (gene-first): TEK(7010):R849W

Genes: TEK(7010)

Variants: R849W

[Paragraph-level] PMCID: PMC2670982 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: R849W | Summary: The R849W mutation is described as an inherited variant associated with a rare form of venous anomalies, indicating it confers inherited risk for disease. Evidence Type: Oncogenic | Mutation: L914F | Summary: The L914F mutation is identified as a somatic variant contributing to tumor development, as it is associated with loss-of-function of the TIE2 receptor in a resected venous malformation. Evidence Type: Functional | Mutation: L914F | Summary: The L914F mutation alters molecular function, as it shows ligand-independent hyperphosphorylation and abnormal localization in endothelial cells when overexpressed.

Gene→Variant (gene-first): 284:L914F 7010:R849W

Genes: 284 7010

Variants: L914F R849W

[Paragraph-level] PMCID: PMC2670982 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Justification: Predisposing: The passage describes germline substitutions in the TIE2/TEK receptor that cause a rare inherited form of venous anomalies, indicating that these variants confer inherited risk for developing the disease. Oncogenic: The passage discusses somatic mutations in TIE2 that contribute to tumor development, specifically noting the identification of somatic mutations in lesions and their role in the etiology of sporadic venous malformations. Functional: The passage mentions that the L914F variant shows ligand-independent hyperphosphorylation and abnormal localization when overexpressed, indicating that it alters molecular function.

Gene→Variant (gene-first): 284:L914F 7010:R849W

Genes: 284 7010

Variants: L914F R849W

[Paragraph-level] PMCID: PMC4845427 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predisposing

Justification: Predisposing: The passage discusses germline RUNX1 alterations identified in pedigrees, indicating inherited risk for developing disease.

Gene→Variant (gene-first): 861:A to I

Genes: 861

Variants: A to I

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 29

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The variant K720E is implicated in a 6-fold increased risk of prostate cancer, indicating its role in inherited risk for developing the disease. Functional: The passage discusses how mutations K720E and R726L impair binding of co-regulatory proteins and disrupt interactions, indicating that these variants alter molecular function. Additionally, N756's mutation to aspartate resulted in complete loss of function, further supporting its functional impact.

Gene→Variant (gene-first): 367:A765T 9611:K720E 367:N756 367:Q902 367:Q902R 367:R726L 367:Y763C 9611:lysine 720

Genes: 367 9611

Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 29

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The variant K720E is implicated in a 6-fold increased risk of prostate cancer, indicating its role in inherited risk for developing the disease. Functional: The passage discusses how mutations K720E and R726L impair binding of co-regulatory proteins and disrupt interactions, indicating that these variants alter molecular function. Additionally, N756's mutation to aspartate resulted in complete loss of function, further supporting its functional impact.

Gene→Variant (gene-first): 367:A765T 9611:K720E 367:N756 367:Q902 367:Q902R 367:R726L 367:Y763C 9611:lysine 720

Genes: 367 9611

Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Justification: Diagnostic: The variant 415 T>C is associated with thrombocytopenia and leukemia, as it was identified in all affected family members and absent in unaffected individuals, indicating its role in defining the disease. Predisposing: The passage describes the variant as being present in affected individuals and absent in unaffected individuals, suggesting it confers inherited risk for developing the disease, although it does not explicitly state that it is germline. Oncogenic: The variant is described in the context of leukemia, indicating its potential role in tumor development or progression, particularly as it is a missense mutation in a gene associated with leukemia.

Gene→Variant (gene-first): 10320:415 T>C 2120:L349P 2120:c. T1046C 2120:proline for leucine at codon 349

Genes: 10320 2120

Variants: 415 T>C L349P c. T1046C proline for leucine at codon 349

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The passage discusses inherited mutations in ETV6 that confer susceptibility to acute leukemia, indicating a germline origin and inherited risk for developing the disease. Functional: The passage describes how the ETV6 mutations (L349P and N385fs) alter the protein's localization and its ability to regulate gene expression, demonstrating a change in molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Justification: Predisposing: The passage describes a germline ETV6 p. L349P mutation identified in a kindred affected by thrombocytopenia and ALL, indicating an inherited risk for developing the disease. Oncogenic: The ETV6 p. N385fs mutation was found in leukemic cells and is associated with the deletion of wild type ETV6, suggesting its contribution to tumor development in the context of leukemia. Functional: The enforced expression of the ETV6 mutants showed impaired nuclear localization and a significantly reduced ability to regulate the transcription of ETV6 target genes, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2120:p. L349P 2120:p. N385fs

Genes: 2120

Variants: p. L349P p. N385fs

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Justification: Diagnostic: The variant 415 T>C is associated with thrombocytopenia and leukemia, as it was identified in all affected family members and absent in unaffected individuals, indicating its role in defining the disease. Predisposing: The passage describes the variant as being present in affected individuals and absent in unaffected individuals, suggesting it confers inherited risk for developing the disease, although it does not explicitly state that it is germline. Oncogenic: The variant is described in the context of leukemia, indicating its potential role in tumor development or progression, particularly as it is a missense mutation in a gene associated with leukemia.

Gene→Variant (gene-first): 10320:415 T>C 2120:L349P 2120:c. T1046C 2120:proline for leucine at codon 349

Genes: 10320 2120

Variants: 415 T>C L349P c. T1046C proline for leucine at codon 349

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The passage discusses inherited mutations in ETV6 that confer susceptibility to acute leukemia, indicating a germline origin and inherited risk for developing the disease. Functional: The passage describes how the ETV6 mutations (L349P and N385fs) alter the protein's localization and its ability to regulate gene expression, demonstrating a change in molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Justification: Predisposing: The passage describes a germline ETV6 p. L349P mutation identified in a kindred affected by thrombocytopenia and ALL, indicating an inherited risk for developing the disease. Oncogenic: The ETV6 p. N385fs mutation was found in leukemic cells and is associated with the deletion of wild type ETV6, suggesting its contribution to tumor development in the context of leukemia. Functional: The enforced expression of the ETV6 mutants showed impaired nuclear localization and a significantly reduced ability to regulate the transcription of ETV6 target genes, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2120:p. L349P 2120:p. N385fs

Genes: 2120

Variants: p. L349P p. N385fs

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage states that the variants are recorded as disease-associated variants, indicating their use in defining or classifying diseases such as diabetes, carotid intima media thickness, and oligospermia. Predisposing: The variants mentioned are associated with inherited conditions, suggesting they confer an inherited risk for developing diseases, although the germline nature is implied rather than explicitly stated.

Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110

Genes: 440822 6289 3767 6833

Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing, Diagnostic

Justification: Predisposing: The passage discusses variants in hereditary loci, specifically mentioning TP53 and BRCA2, which are associated with inherited cancer syndromes, indicating a potential inherited risk for developing disease. Diagnostic: The passage mentions the classification of variants as "Benign" or of "Uncertain significance," which relates to their use in defining or classifying disease risk or status.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage states that the variants are recorded as disease-associated variants, indicating their use in defining or classifying diseases such as diabetes, carotid intima media thickness, and oligospermia. Predisposing: The variants mentioned are associated with inherited conditions, suggesting they confer an inherited risk for developing diseases, although the germline nature is implied rather than explicitly stated.

Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110

Genes: 440822 6289 3767 6833

Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing, Diagnostic

Justification: Predisposing: The passage discusses variants in hereditary loci, specifically mentioning TP53 and BRCA2, which are associated with inherited cancer syndromes, indicating a potential inherited risk for developing disease. Diagnostic: The passage mentions the classification of variants as "Benign" or of "Uncertain significance," which relates to their use in defining or classifying disease risk or status.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predisposing, Oncogenic

Justification: Predisposing: The passage describes a germline mutation (p.R1276*) associated with an autosomal dominant tumor predisposition syndrome, indicating inherited risk for developing gliomas. Oncogenic: The passage discusses the somatic inactivation of the remaining wild-type NF1 allele, which contributes to tumor development in gliomas, indicating that the variant plays a role in oncogenesis.

Gene→Variant (gene-first): 4763:c.4110 + 2 T > G 4763:p.R1276*

Genes: 4763

Variants: c.4110 + 2 T > G p.R1276*

[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predisposing, Oncogenic

Justification: Predisposing: The passage describes a germline mutation (p.R1276*) associated with an autosomal dominant tumor predisposition syndrome, indicating inherited risk for developing gliomas. Oncogenic: The passage discusses the somatic inactivation of the remaining wild-type NF1 allele, which contributes to tumor development in gliomas, indicating that the variant plays a role in oncogenesis.

Gene→Variant (gene-first): 4763:c.4110 + 2 T > G 4763:p.R1276*

Genes: 4763

Variants: c.4110 + 2 T > G p.R1276*

[Paragraph-level] PMCID: PMC7342819 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Justification: Diagnostic: The passage discusses the identification of the KRAS p.G12V mutation and the PALB2 mutations in the context of a primary lesion, indicating their association with the disease. Predisposing: The PALB2 c.3114-1G>A mutation is explicitly described as a germline mutation detected in peripheral blood cells, suggesting it confers inherited risk for developing disease. Oncogenic: The PALB2 c.2514+1G>C mutation is described as a somatic mutation, which is associated with tumor development in the context of the primary lesion.

Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A 3845:p.G12V

Genes: 79728 3845

Variants: c.2514+1G>C c.3114-1G>A p.G12V

[Paragraph-level] PMCID: PMC7342819 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Justification: Diagnostic: The passage discusses the identification of the KRAS p.G12V mutation and the PALB2 mutations in the context of a primary lesion, indicating their association with the disease. Predisposing: The PALB2 c.3114-1G>A mutation is explicitly described as a germline mutation detected in peripheral blood cells, suggesting it confers inherited risk for developing disease. Oncogenic: The PALB2 c.2514+1G>C mutation is described as a somatic mutation, which is associated with tumor development in the context of the primary lesion.

Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A 3845:p.G12V

Genes: 79728 3845

Variants: c.2514+1G>C c.3114-1G>A p.G12V

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Predisposing

Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.

Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L

Genes: 1956

Variants: A289 A289D A289T E330K L861Q R108 R324L

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Predisposing

Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.

Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L

Genes: 1956

Variants: A289 A289D A289T E330K L861Q R108 R324L

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses individuals with mosaic PIK3CA mutations, including the p.Glu726Lys variant, in the context of classic features of MCAP, indicating its role in defining or classifying the disease. Predisposing: The passage mentions that several patients with the p.Glu726Lys mutation had various clinical findings associated with MCAP, suggesting an inherited risk for developing this condition.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses individuals with mosaic PIK3CA mutations, including the p.Glu726Lys variant, in the context of classic features of MCAP, indicating its role in defining or classifying the disease. Predisposing: The passage mentions that several patients with the p.Glu726Lys mutation had various clinical findings associated with MCAP, suggesting an inherited risk for developing this condition.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses the recurrent alteration of RIT1 alanine 77 and mentions that one of the mutated samples harbored a p.A77P mutation, indicating its association with tumor classification. Predisposing: The passage suggests that p.A77S may represent a rare germline variant, indicating a potential inherited risk for disease, although it is noted to be unlikely.

Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S

Genes: NA 6016

Variants: alanine 77 p.A77P p.A77S

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses the recurrent alteration of RIT1 alanine 77 and mentions that one of the mutated samples harbored a p.A77P mutation, indicating its association with tumor classification. Predisposing: The passage suggests that p.A77S may represent a rare germline variant, indicating a potential inherited risk for disease, although it is noted to be unlikely.

Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S

Genes: NA 6016

Variants: alanine 77 p.A77P p.A77S

[Paragraph-level] PMCID: PMC3184204 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Diagnostic, Functional

Justification: Predisposing: The passage describes the discovery of the GATA2 gene as a predisposition gene for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating that the variants are associated with inherited risk for developing these diseases. Diagnostic: The variants are used to define and classify familial forms of MDS and AML, as they are reported to segregate with the disease in multiple families, which supports their role in diagnosis. Functional: The passage mentions that the mutations have differential effects on transactivation of target genes, cellular differentiation, apoptosis, and global gene expression, indicating that they alter molecular or biochemical function.

Gene→Variant (gene-first): 2624:c.1061C>T 2624:c.1063_1065delACA 2624:p.Thr354Met 6688:p.Thr355del

Genes: 2624 6688

Variants: c.1061C>T c.1063_1065delACA p.Thr354Met p.Thr355del

[Paragraph-level] PMCID: PMC3184204 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Diagnostic, Functional

Justification: Predisposing: The passage describes the discovery of the GATA2 gene as a predisposition gene for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating that the variants are associated with inherited risk for developing these diseases. Diagnostic: The variants are used to define and classify familial forms of MDS and AML, as they are reported to segregate with the disease in multiple families, which supports their role in diagnosis. Functional: The passage mentions that the mutations have differential effects on transactivation of target genes, cellular differentiation, apoptosis, and global gene expression, indicating that they alter molecular or biochemical function.

Gene→Variant (gene-first): 2624:c.1061C>T 2624:c.1063_1065delACA 2624:p.Thr354Met 6688:p.Thr355del

Genes: 2624 6688

Variants: c.1061C>T c.1063_1065delACA p.Thr354Met p.Thr355del