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.4185G>C (p.Gln1395His)

CA10580532

232793 (ClinVar)

Gene: BRCA1 (HGNC:672)

Condition: BRCA1-related cancer predisposition (MONDO:0700268)

Inheritance Mode: Autosomal dominant inheritance

UUID: 9ef5ebb6-b717-4061-8655-b7c3bf79b9a5

Approved on: 2026-03-19

Published on: 2026-03-19

HGVS expressions

NM_007294.4(BRCA1):c.4185G>C (p.Gln1395His)

NM_007294.4:c.4185G>C

NC_000017.11:g.43090944C>G

CM000679.2:g.43090944C>G

NC_000017.10:g.41242961C>G

CM000679.1:g.41242961C>G

NC_000017.9:g.38496487C>G

NG_005905.2:g.127040G>C

ENST00000461574.2:c.4185G>C

ENST00000470026.6:c.4185G>C

ENST00000473961.6:c.4059G>C

ENST00000476777.6:c.4182G>C

ENST00000477152.6:c.4107G>C

ENST00000478531.6:c.873G>C

ENST00000489037.2:c.4107G>C

ENST00000493919.6:c.735G>C

ENST00000494123.6:c.4185G>C

ENST00000497488.2:c.3297G>C

ENST00000618469.2:c.4185G>C

ENST00000634433.2:c.4062G>C

ENST00000644379.2:c.4185G>C

ENST00000644555.2:c.735G>C

ENST00000652672.2:c.4044G>C

ENST00000484087.6:c.753G>C

ENST00000700182.1:c.795G>C

ENST00000357654.9:c.4185G>C

ENST00000471181.7:c.4185G>C

ENST00000644379.1:c.506G>C

ENST00000352993.7:c.759G>C

ENST00000357654.7:c.4185G>C

ENST00000461221.5:c.*3968G>C

ENST00000461574.1:c.479G>C

ENST00000468300.5:c.876G>C

ENST00000471181.6:c.4185G>C

ENST00000478531.5:c.873G>C

ENST00000484087.5:c.498G>C

ENST00000487825.5:c.501G>C

ENST00000491747.6:c.876G>C

ENST00000493795.5:c.4044G>C

ENST00000493919.5:c.735G>C

ENST00000586385.5:c.5-26993G>C

ENST00000591534.5:c.-43-16423G>C

ENST00000591849.5:c.-99+34327G>C

NM_007294.3:c.4185G>C

NM_007297.3:c.4044G>C

NM_007298.3:c.876G>C

NM_007299.3:c.876G>C

NM_007300.3:c.4185G>C

NR_027676.1:n.4321G>C

NM_007297.4:c.4044G>C

NM_007299.4:c.876G>C

NM_007300.4:c.4185G>C

NR_027676.2:n.4362G>C

Likely Pathogenic

PM2_Supporting PP3 PS1

PVS1

Evidence Links 0

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.4185G>C variant in BRCA1 is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 1395 (p.(Gln1395His)). This is the last nucleotide of the exon. 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 BRCA1 missense variant has a SpliceAI score of 0.95, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by skipping of exon 12 (PMID: 29750258). The percent reference (full length) and aberrant transcripts produced from the variant allele is not stated (PVS1_N/A (RNA)). The variant under assessment is located outside the canonical dinucleotide, and has been assigned PP3 based on splicing predictions. Another variant at the same nucleotide position (c.4185G>A) is classified as pathogenic by the ENIGMA BRCA1/2 VCEP. The SpliceAI predictions indicate that the two variants are likely to lead to the same event (disruption of the donor splice site of intron 11(12) in BRCA1). These observations suggest that the variant has an impact on splicing consistent with pathogenicity (PS1 (Splicing) met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS1 (Splicing)).

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).

PP3

This BRCA1 missense variant has a SpliceAI score of 0.95, predicting an impact on splicing (score threshold >0.20) (PP3 met).

PS1

The variant under assessment is located outside the canonical dinucleotide, and has been assigned PP3 based on splicing predictions. Another variant at the same nucleotide position (c.4185G>A) is classified as pathogenic by the ENIGMA BRCA1/2 VCEP. The SpliceAI predictions indicate that the two variants are likely to lead to the same event (disruption of the donor splice site of intron 11(12) in BRCA1). These observations suggest that the variant has an impact on splicing consistent with pathogenicity (PS1 (Splicing) met).

PVS1

This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by skipping of exon 12 (PMID: 29750258). The percent reference (full length) and aberrant transcripts produced from the variant allele is not stated (PVS1_N/A (RNA)).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.