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.4211T>G (p.Leu1404Arg)

CA059655

491071 (ClinVar)

Gene: BRCA1 (HGNC:672)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: d18a7e33-2187-4ff7-a147-eadb7ab11b60

Approved on: 2025-12-03

Published on: 2025-12-02

HGVS expressions

NM_007294.4(BRCA1):c.4211T>G (p.Leu1404Arg)

NM_007294.4:c.4211T>G

NC_000017.11:g.43082550A>C

CM000679.2:g.43082550A>C

NC_000017.10:g.41234567A>C

CM000679.1:g.41234567A>C

NC_000017.9:g.38488093A>C

NG_005905.2:g.135434T>G

ENST00000461574.2:c.4211T>G

ENST00000470026.6:c.4211T>G

ENST00000473961.6:c.4085T>G

ENST00000476777.6:c.4205T>G

ENST00000477152.6:c.4133T>G

ENST00000478531.6:c.899T>G

ENST00000489037.2:c.4133T>G

ENST00000493919.6:c.761T>G

ENST00000494123.6:c.4211T>G

ENST00000497488.2:c.3323T>G

ENST00000618469.2:c.4211T>G

ENST00000634433.2:c.4088T>G

ENST00000644379.2:c.4211T>G

ENST00000644555.2:c.761T>G

ENST00000652672.2:c.4070T>G

ENST00000484087.6:c.776T>G

ENST00000700182.1:c.821T>G

ENST00000357654.9:c.4211T>G

ENST00000471181.7:c.4211T>G

ENST00000644379.1:c.532T>G

ENST00000352993.7:c.785T>G

ENST00000357654.7:c.4211T>G

ENST00000461221.5:c.*3994T>G

ENST00000461574.1:c.505T>G

ENST00000468300.5:c.902T>G

ENST00000471181.6:c.4211T>G

ENST00000478531.5:c.899T>G

ENST00000484087.5:c.524T>G

ENST00000487825.5:c.527T>G

ENST00000491747.6:c.902T>G

ENST00000493795.5:c.4070T>G

ENST00000493919.5:c.761T>G

ENST00000586385.5:c.5-18599T>G

ENST00000591534.5:c.-43-8029T>G

ENST00000591849.5:c.-98-32360T>G

ENST00000621897.1:n.105T>G

NM_007294.3:c.4211T>G

NM_007297.3:c.4070T>G

NM_007298.3:c.902T>G

NM_007299.3:c.902T>G

NM_007300.3:c.4211T>G

NR_027676.1:n.4347T>G

NM_007297.4:c.4070T>G

NM_007299.4:c.902T>G

NM_007300.4:c.4211T>G

NR_027676.2:n.4388T>G

Uncertain Significance

BP4 PM2_Supporting PP1

PP3

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.4211T>G variant in BRCA1 is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 1404 (p.(Leu1404Arg)). This variant is absent from gnomAD v4.1 (read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.09, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (BP4 met). Cosegregation analysis of one family carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 3.9 (applied as LR), within the thresholds for supporting pathogenic evidence (LR ≥2.08 & <4.3) (PP1 met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, PM2_Supporting, PP1).

BP4

This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.09, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (BP4 met).

PM2_Supporting

This variant is absent from gnomAD v4.1 (read depth ≥25) (PM2_Supporting met).

PP1

Cosegregation analysis of one family carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 3.9 (applied as LR), within the thresholds for supporting pathogenic evidence (LR ≥2.08 & <4.3) (PP1 met; Internal lab contributor).

PP3

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

Curation History

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