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.4159T>C (p.Ser1387Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10575944

224433 (ClinVar)

Gene: BRCA1

Condition: BRCA1-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9c48d2a8-1cec-4a03-88ae-2d943288ce71

Approved on: 2025-05-23

Published on: 2025-05-23

HGVS expressions

NM_007294.4:c.4159T>C

NM_007294.4(BRCA1):c.4159T>C (p.Ser1387Pro)

NC_000017.11:g.43090970A>G

CM000679.2:g.43090970A>G

NC_000017.10:g.41242987A>G

CM000679.1:g.41242987A>G

NC_000017.9:g.38496513A>G

NG_005905.2:g.127014T>C

ENST00000461574.2:c.4159T>C

ENST00000470026.6:c.4159T>C

ENST00000473961.6:c.4033T>C

ENST00000476777.6:c.4156T>C

ENST00000477152.6:c.4081T>C

ENST00000478531.6:c.847T>C

ENST00000489037.2:c.4081T>C

ENST00000493919.6:c.709T>C

ENST00000494123.6:c.4159T>C

ENST00000497488.2:c.3271T>C

ENST00000618469.2:c.4159T>C

ENST00000634433.2:c.4036T>C

ENST00000644379.2:c.4159T>C

ENST00000644555.2:c.709T>C

ENST00000652672.2:c.4018T>C

ENST00000484087.6:c.727T>C

ENST00000700182.1:c.769T>C

ENST00000357654.9:c.4159T>C

ENST00000471181.7:c.4159T>C

ENST00000644379.1:c.480T>C

ENST00000352993.7:c.733T>C

ENST00000357654.7:c.4159T>C

ENST00000461221.5:c.*3942T>C

ENST00000461574.1:c.453T>C

ENST00000468300.5:c.850T>C

ENST00000471181.6:c.4159T>C

ENST00000478531.5:c.847T>C

ENST00000484087.5:c.472T>C

ENST00000487825.5:c.475T>C

ENST00000491747.6:c.850T>C

ENST00000493795.5:c.4018T>C

ENST00000493919.5:c.709T>C

ENST00000586385.5:c.5-27019T>C

ENST00000591534.5:c.-43-16449T>C

ENST00000591849.5:c.-99+34301T>C

NM_007294.3:c.4159T>C

NM_007297.3:c.4018T>C

NM_007298.3:c.850T>C

NM_007299.3:c.850T>C

NM_007300.3:c.4159T>C

NR_027676.1:n.4295T>C

NM_007297.4:c.4018T>C

NM_007299.4:c.850T>C

NM_007300.4:c.4159T>C

NR_027676.2:n.4336T>C

Likely Benign

BP1_Strong BP5

PM2 BS3 BS1 PS3

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 BRCA1 Version 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.4159T>C variant in BRCA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 1387 (p.Ser1387Pro). 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 missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.00, score threshold ≤0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.364 (based on Family History LR=0.364), within the thresholds for supporting benign evidence (LR >0.23 & ≤0.48) (BP5 met; PMID 31853058). In summary, this variant meets the criteria to be classified as a likely benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BP5).

BP1_Strong

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

BP5

Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.364 (based on Family History LR=0.364), within the thresholds for supporting benign evidence (LR >0.23 & ≤0.48) (BP5 met; PMID 31853058).

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No calibrated studies were performed for this variant.

BS1

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).

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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