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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000059.4(BRCA2):c.7521A>G (p.Pro2507=)

CA025129

184061 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 068fbe75-2846-472c-8fdd-ba17ace48963

Approved on: 2024-06-12

Published on: 2024-06-12

HGVS expressions

NM_000059.4:c.7521A>G

NM_000059.4(BRCA2):c.7521A>G (p.Pro2507=)

NC_000013.11:g.32356513A>G

CM000675.2:g.32356513A>G

NC_000013.10:g.32930650A>G

CM000675.1:g.32930650A>G

NC_000013.9:g.31828650A>G

NG_012772.3:g.46034A>G

ENST00000470094.2:c.7521A>G

ENST00000528762.2:c.7521A>G

ENST00000530893.7:c.7152A>G

ENST00000665585.2:c.7521A>G

ENST00000666593.2:c.7521A>G

ENST00000700202.2:c.7521A>G

ENST00000380152.8:c.7521A>G

ENST00000544455.6:c.7521A>G

ENST00000614259.2:c.7521A>G

ENST00000665585.1:c.86A>G

ENST00000680887.1:c.7521A>G

ENST00000380152.7:c.7521A>G

ENST00000544455.5:c.7521A>G

ENST00000614259.1:n.7521A>G

NM_000059.3:c.7521A>G

Benign

BP7_Strong BP5_Strong BS1 BP4

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.7521A>G variant in BRCA2 is a synonymous variant (p.Pro2507=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003057 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 24489791), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.01 (based on Cosegregation LR=0.01), within the thresholds for Strong benign evidence (LR ≥0.00285 & <0.05) (BP5_Strong met; PMID: 24489791). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP4, BP7_Strong (RNA), BP5_Strong).

BP7_Strong

This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 24489791), considered strong evidence against pathogenicity (BP7_Strong (RNA)).

BP5_Strong

Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.01 (based on Cosegregation LR=0.01), within the thresholds for Strong benign evidence (LR ≥0.00285 & <0.05) (BP5_Strong met; PMID: 24489791).

BS1

The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003057 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met).

BP4

This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met).

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