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_007294.4(BRCA1):c.305C>G (p.Ala102Gly)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA002009

37505 (ClinVar)

Gene: BRCA1

Condition: BRCA1-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: de5081dd-8e3e-444d-9826-44632cbee0f3

Approved on: 2024-06-12

Published on: 2024-06-11

HGVS expressions

NM_007294.4:c.305C>G

NM_007294.4(BRCA1):c.305C>G (p.Ala102Gly)

NC_000017.11:g.43104258G>C

CM000679.2:g.43104258G>C

NC_000017.10:g.41256275G>C

CM000679.1:g.41256275G>C

NC_000017.9:g.38509801G>C

NG_005905.2:g.113726C>G

ENST00000354071.8:n.369C>G

ENST00000461574.2:c.305C>G

ENST00000470026.6:c.305C>G

ENST00000473961.6:c.305C>G

ENST00000476777.6:c.305C>G

ENST00000477152.6:c.227C>G

ENST00000478531.6:c.305C>G

ENST00000489037.2:c.227C>G

ENST00000493919.6:c.164C>G

ENST00000494123.6:c.305C>G

ENST00000497488.2:c.-218-9398C>G

ENST00000618469.2:c.305C>G

ENST00000634433.2:c.305C>G

ENST00000644379.2:c.305C>G

ENST00000644555.2:c.164C>G

ENST00000652672.2:c.164C>G

ENST00000484087.6:c.305C>G

ENST00000700083.1:n.1276C>G

ENST00000700182.1:c.227C>G

ENST00000700183.1:c.*219C>G

ENST00000700184.1:n.548C>G

ENST00000357654.9:c.305C>G

ENST00000471181.7:c.305C>G

ENST00000642945.1:c.*179C>G

ENST00000644555.1:c.164C>G

ENST00000652672.1:c.164C>G

ENST00000352993.7:c.305C>G

ENST00000354071.7:c.305C>G

ENST00000357654.7:c.305C>G

ENST00000461221.5:c.*91C>G

ENST00000461798.5:c.*91C>G

ENST00000468300.5:c.305C>G

ENST00000470026.5:c.305C>G

ENST00000471181.6:c.305C>G

ENST00000473961.5:c.28C>G

ENST00000476777.5:c.305C>G

ENST00000477152.5:c.227C>G

ENST00000478531.5:c.305C>G

ENST00000484087.5:c.53C>G

ENST00000487825.5:c.53C>G

ENST00000489037.1:c.227C>G

ENST00000491747.6:c.305C>G

ENST00000492859.5:c.*241C>G

ENST00000493795.5:c.164C>G

ENST00000493919.5:c.164C>G

ENST00000494123.5:c.305C>G

ENST00000497488.1:c.-218-9398C>G

ENST00000586385.5:c.4+20924C>G

ENST00000591534.5:c.-44+21013C>G

ENST00000591849.5:c.-99+21013C>G

ENST00000634433.1:c.305C>G

NM_007294.3:c.305C>G

NM_007297.3:c.164C>G

NM_007298.3:c.305C>G

NM_007299.3:c.305C>G

NM_007300.3:c.305C>G

NR_027676.1:n.444C>G

NM_007297.4:c.164C>G

NM_007299.4:c.305C>G

NM_007300.4:c.305C>G

NR_027676.2:n.485C>G

Benign

BS3 PM2_Supporting BP5_Strong BP1_Strong

Evidence Links 1

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 BRCA1 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.305C>G variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 102 (p.Ala102Gly). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.00, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30219179) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.015 (based on Co-occurrence LR=1.177; Family History LR=0.0127), below the threshold for strong benign evidence (LR <0.05) (BP5_Strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP1_Strong, BS3, BP5_Strong).

BS3

Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30219179) (BS3 met).

Functional PubMed:30219179

PM2_Supporting

This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).

BP5_Strong

Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.015 (based on Co-occurrence LR=1.177; Family History LR=0.0127), below the threshold for strong benign evidence (LR <0.05) (BP5_Strong met; PMID: 31131967).

BP1_Strong

This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.00, score threshold <0.1) (BP1_Strong met).

Curation History

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