Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000059.4(BRCA2):c.7977-1G>C

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA025372

38132 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9c75627c-0e4b-4cd2-8dd4-37371b31c1bc

Approved on: 2024-06-12

Published on: 2024-06-12

HGVS expressions

NM_000059.4:c.7977-1G>C

NM_000059.4(BRCA2):c.7977-1G>C

NC_000013.11:g.32363178G>C

CM000675.2:g.32363178G>C

NC_000013.10:g.32937315G>C

CM000675.1:g.32937315G>C

NC_000013.9:g.31835315G>C

NG_012772.3:g.52699G>C

ENST00000470094.2:c.7977-1G>C

ENST00000528762.2:c.7977-1G>C

ENST00000530893.7:c.7608-1G>C

ENST00000665585.2:c.7977-1G>C

ENST00000666593.2:c.7977-1G>C

ENST00000700202.2:c.7977-1G>C

ENST00000700202.1:c.444-1G>C

ENST00000380152.8:c.7977-1G>C

ENST00000544455.6:c.7977-1G>C

ENST00000614259.2:c.7985-1G>C

ENST00000665585.1:c.542-1G>C

ENST00000680887.1:c.7977-1G>C

ENST00000380152.7:c.7977-1G>C

ENST00000544455.5:c.7977-1G>C

NM_000059.3:c.7977-1G>C

Pathogenic

PVS1 PP4_Strong

BA1 PM2 BS1

Evidence Links 0

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.7977-1G>C variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 17 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1921581780 (based on Cosegregation LR=1984740; Pathology LR=10.2; Family History LR=94.9), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong).

PVS1

This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met).

PP4_Strong

Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1921581780 (based on Cosegregation LR=1984740; Pathology LR=10.2; Family History LR=94.9), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, Internal lab contributors).

BA1

This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).

PM2

BS1

Curation History

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