[Paper-level Aggregated] PMCID: PMC4477877

Evidence Type(s): Functional

Summary: Mutation: L349P | Summary: The L349P mutation alters the localization and molecular function of the ETV6 protein, preventing it from localizing to the nucleus, impacting its regulatory function, and resulting in significantly decreased transcriptional repression compared to wild-type ETV6. It is also predicted to cause significant conformational changes and affects translation and subcellular localization.

Evidence Type: Functional Mutation: N385fs | Summary: The N385fs mutation results in an abnormally truncated ETV6 protein, impairing its ability to regulate the expression of target genes and exhibiting significantly decreased transcriptional repression compared to wild-type ETV6. It is also predicted to truncate the protein at a region involved in DNA interaction, suggesting a change in its biochemical function and affecting translation and subcellular localization.

Evidence Type: Functional Mutation: P214L | Summary: The P214L mutation demonstrates significantly decreased transcriptional repression compared to wild-type ETV6 and is detectable in both cytoplasmic and nuclear fractions, indicating a potential alteration in molecular function.

Evidence Type: Functional Mutation: R369Q | Summary: The R369Q mutation shows significantly reduced transcriptional repression compared to wild-type ETV6 and is present in both cytoplasmic and nuclear fractions, suggesting an alteration in molecular function.

Evidence Type: Functional Mutation: R399C | Summary: The R399C mutation exhibits significantly decreased transcriptional repression compared to wild-type ETV6 and is detectable in both cytoplasmic and nuclear fractions, indicating a potential change in molecular function.

Gene→Variant (gene-first): ETV6(2120):L349P ETV6(2120):N385fs ETV6(2120):P214L ETV6(2120):R369Q ETV6(2120):R399C

Genes: ETV6(2120)

Variants: L349P N385fs P214L R369Q R399C

[Paper-level Aggregated] PMCID: PMC4477877

Evidence Type(s): Oncogenic

Summary: Mutation: p. N385fs | Summary: The p. N385fs mutation was found in leukemic cells and is associated with tumor development in acute lymphoblastic leukemia (ALL) and secondary myelodysplasia/acute myeloid leukemia, contributing to tumor development.

Evidence Type: Oncogenic Mutation: 415 T>C | Summary: The 415 T>C variant is a somatic mutation that contributes to tumor development, as it is present in all affected family members tested.

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 found in patients with B-ALL, suggesting its involvement in tumor progression.

Gene→Variant (gene-first): ETV6(2120):p. N385fs IKZF1(10320):415 T>C ETV6(2120):V37M ETV6(2120):R181H

Genes: ETV6(2120) IKZF1(10320)

Variants: p. N385fs 415 T>C V37M R181H

[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

[Paper-level Aggregated] PMCID: PMC4477877

Evidence Type(s): Diagnostic

Summary: Mutation: 415 T>C | Summary: The variant 415 T>C is associated with the diagnosis of thrombocytopenia and/or ALL, as it co-segregates with affected individuals in the family.

Gene→Variant (gene-first): IKZF1(10320):415 T>C

Genes: IKZF1(10320)

Variants: 415 T>C

[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: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation is evaluated for its impact on translation and subcellular localization of the ETV6 protein, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation is assessed for its effect on translation and subcellular localization of the ETV6 protein, suggesting a change in molecular function. Evidence Type: Functional | Mutation: P214L | Summary: The P214L mutation is described as being detectable in both cytoplasmic and nuclear fractions, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: R369Q | Summary: The R369Q mutation is noted for its presence in both cytoplasmic and nuclear fractions, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: R399C | Summary: The R399C mutation is mentioned as being detectable in both cytoplasmic and nuclear fractions, indicating a potential change in molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation was assessed for its impact on transcriptional repression by ETV6, showing significantly decreased repression compared to wild-type ETV6. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation was evaluated for its ability to impair transcriptional repression by ETV6, exhibiting significantly decreased repression relative to wild-type ETV6. Evidence Type: Functional | Mutation: P214L | Summary: The P214L mutation, a germline variant, was compared to other ETV6 mutations and demonstrated significantly decreased transcriptional repression compared to wild-type ETV6. Evidence Type: Functional | Mutation: R369Q | Summary: The R369Q mutation was analyzed alongside other ETV6 variants and showed significantly reduced transcriptional repression compared to wild-type ETV6. Evidence Type: Functional | Mutation: R399C | Summary: The R399C mutation was included in the analysis of ETV6 variants and exhibited significantly decreased transcriptional repression compared to wild-type ETV6.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation is predicted to cause significant conformational changes in the ETV6 protein, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation is predicted to truncate the ETV6 protein at a region involved in DNA interaction, indicating a change in its biochemical function.

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

Genes: 2120

Variants: L349P N385fs

[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: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic, Functional

Summary: Evidence Type: Diagnostic | Mutation: 415 T>C | Summary: The variant 415 T>C is associated with the diagnosis of thrombocytopenia and/or ALL, as it co-segregates with affected individuals in the family. Evidence Type: Oncogenic | Mutation: 415 T>C | Summary: The 415 T>C variant is a somatic mutation that contributes to tumor development, as it is present in all affected family members tested. Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation results in a substitution that alters the molecular function of the ETV6 protein, impacting its role in cellular processes.

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

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: PMC4477877

Evidence Type(s): Predisposing, Functional, Oncogenic

Justification: Predisposing: The identification of germline ETV6 mutations, such as L349P and N385fs, in kindreds affected by thrombocytopenia and acute lymphoblastic leukemia (ALL) suggests a hereditary predisposition to leukemia. Functional: The study demonstrates that the ETV6 mutations impair nuclear localization and transcriptional regulation of ETV6 target genes, indicating a functional impact on the protein's ability to perform its role as a transcription factor. Oncogenic: The presence of ETV6 mutations in individuals with ALL and their association with leukemic phenotypes suggest that these mutations may contribute to oncogenesis in the context of leukemia.

Gene→Variant (gene-first): ETV6(2120):11905459G>A ETV6(2120):12022436 G>A ETV6(2120):R181H ETV6(2120):V37M ETV6(2120):rs150089916 IKZF1(10320):415 T>C ETV6(2120):L349P ETV6(2120):c. T1046C ETV6(2120):proline for leucine at codon 349 ETV6(2120):N385fs ETV6(2120):P214L ETV6(2120):R369Q ETV6(2120):R399C ETV6(2120):c.1153-5_1153_1delAACAG ETV6(2120):p. L349P ETV6(2120):p. N385fs

Genes: ETV6(2120) IKZF1(10320)

Variants: 11905459G>A 12022436 G>A R181H V37M rs150089916 415 T>C L349P c. T1046C proline for leucine at codon 349 N385fs P214L R369Q R399C c.1153-5_1153_1delAACAG p. L349P p. N385fs

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

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of rare germline variants (V37M, R181H) in patients with B-ALL, indicating their association with the disease. Functional: Luciferase assays performed on the variants showed no significant changes in transcriptional repression activity compared to WT ETV6, indicating an assessment of their molecular function.

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: 10

Evidence Type(s): Functional

Justification: Functional: The detection of different localization patterns for the mutants P214L, R369Q, and R399C also suggests alterations in their molecular or biochemical function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the mutations L349P, N385fs, P214L, R369Q, and R399C impair the transcriptional repression function of ETV6, indicating that these variants alter molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the L349P and N385fs mutations are predicted to alter the molecular function of the ETV6 protein, including conformational changes and truncation that affect DNA interaction.

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

Genes: 2120

Variants: L349P N385fs

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

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of a heterozygous deletion in ETV6 that is associated with the diagnosis of acute lymphoblastic leukemia (ALL) in the proband, indicating its role in defining the disease. Oncogenic: The variant N385fs is described as leading to a truncation of the ETV6 protein, which is implicated in tumor development, specifically 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: 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: 12

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of rare germline variants (V37M, R181H) in patients with B-ALL, indicating their association with the disease. Functional: Luciferase assays performed on the variants showed no significant changes in transcriptional repression activity compared to WT ETV6, indicating an assessment of their molecular function.

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: 10

Evidence Type(s): Functional

Justification: Functional: The detection of different localization patterns for the mutants P214L, R369Q, and R399C also suggests alterations in their molecular or biochemical function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the mutations L349P, N385fs, P214L, R369Q, and R399C impair the transcriptional repression function of ETV6, indicating that these variants alter molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the L349P and N385fs mutations are predicted to alter the molecular function of the ETV6 protein, including conformational changes and truncation that affect DNA interaction.

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

Genes: 2120

Variants: L349P N385fs

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

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of a heterozygous deletion in ETV6 that is associated with the diagnosis of acute lymphoblastic leukemia (ALL) in the proband, indicating its role in defining the disease. Oncogenic: The variant N385fs is described as leading to a truncation of the ETV6 protein, which is implicated in tumor development, specifically 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: 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