Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: BRCA1 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • cspec.ruleSetIri property did not resolve into a valid CSPEC request: https://cspec.genome.network/cspec-priv/RuleSet/id/1530970184!
  • cspecId property did not resolve into a valid CSPEC request: https://cspec.genome.network/cspec-priv/SequenceVariantInterpretation/id/1530970171!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_007294.4(BRCA1):c.122A>T (p.His41Leu)

CA10580711

230862 (ClinVar)

Gene: BRCA1
Condition: BRCA1-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: cee13ac0-54b0-48d4-9e9d-6dfcda92e595
Approved on: 2025-05-23
Published on: 2025-05-23

HGVS expressions

NM_007294.4:c.122A>T
NM_007294.4(BRCA1):c.122A>T (p.His41Leu)
NC_000017.11:g.43115738T>A
CM000679.2:g.43115738T>A
NC_000017.10:g.41267755T>A
CM000679.1:g.41267755T>A
NC_000017.9:g.38521281T>A
NG_005905.2:g.102246A>T
ENST00000354071.8:n.186A>T
ENST00000461574.2:c.122A>T
ENST00000470026.6:c.122A>T
ENST00000473961.6:c.122A>T
ENST00000476777.6:c.122A>T
ENST00000477152.6:c.122A>T
ENST00000478531.6:c.122A>T
ENST00000489037.2:c.122A>T
ENST00000493919.6:c.-8+8279A>T
ENST00000494123.6:c.122A>T
ENST00000497488.2:c.-219+9533A>T
ENST00000618469.2:c.122A>T
ENST00000634433.2:c.122A>T
ENST00000644379.2:c.122A>T
ENST00000644555.2:c.-20A>T
ENST00000652672.2:c.-20A>T
ENST00000484087.6:c.122A>T
ENST00000700182.1:c.122A>T
ENST00000700183.1:c.122A>T
ENST00000700184.1:n.365A>T
ENST00000700185.1:n.241A>T
ENST00000357654.9:c.122A>T
ENST00000471181.7:c.122A>T
ENST00000642945.1:c.122A>T
ENST00000644555.1:c.-20A>T
ENST00000652672.1:c.-20A>T
ENST00000352993.7:c.122A>T
ENST00000354071.7:c.122A>T
ENST00000357654.7:c.122A>T
ENST00000461221.5:c.122A>T
ENST00000461798.5:c.122A>T
ENST00000468300.5:c.122A>T
ENST00000470026.5:c.122A>T
ENST00000471181.6:c.122A>T
ENST00000476777.5:c.122A>T
ENST00000477152.5:c.122A>T
ENST00000478531.5:c.122A>T
ENST00000489037.1:c.122A>T
ENST00000491747.6:c.122A>T
ENST00000492859.5:c.122A>T
ENST00000493795.5:c.-8+8279A>T
ENST00000493919.5:c.-8+8279A>T
ENST00000494123.5:c.122A>T
ENST00000497488.1:c.-219+9533A>T
ENST00000586385.5:c.4+9444A>T
ENST00000591534.5:c.-44+9533A>T
ENST00000591849.5:c.-99+9533A>T
ENST00000634433.1:c.122A>T
NM_007294.3:c.122A>T
NM_007297.3:c.-8+8279A>T
NM_007298.3:c.122A>T
NM_007299.3:c.122A>T
NM_007300.3:c.122A>T
NR_027676.1:n.283A>T
NM_007297.4:c.-8+8279A>T
NM_007299.4:c.122A>T
NM_007300.4:c.122A>T
NR_027676.2:n.324A>T
More

Likely Pathogenic

Met criteria codes 3
PS3 PP3 PM2_Supporting
Not Met criteria codes 1
PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.122A>T variant in BRCA1 is a missense variant predicted to cause substitution of histidine by leucine at amino acid 41 (p.(His41Leu)). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.56, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID: 30209399, 35659930). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.78 (based on family history), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). 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). 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 (PP3, PS3, PM2_Supporting).
Met criteria codes
PS3
Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID: 30209399, 35659930).
PP3
This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.56, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1).
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).
Not Met criteria codes
PP4
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.78 (based on the family history), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058).
Curation History
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