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
  • cspecId property did not resolve into a valid CSPEC request: https://cspec.genome.network/cspec-priv/SequenceVariantInterpretation/id/1530970171!
  • cspec.ruleSetIri property did not resolve into a valid CSPEC request: https://cspec.genome.network/cspec-priv/RuleSet/id/1530970184!
  • No CSPEC computed assertion could be determined for this classification!
  • No Criteria Specification was provided in the publication event for the variant classifaction.
  • The Criteria Specification shown below is a best-estimate based on the VCEP, gene, disease, and publication date.

Variant: NM_007294.4(BRCA1):c.101C>T (p.Pro34Leu)

CA000691

186913 (ClinVar)

Gene: BRCA1 (HGNC:672)
Condition: BRCA1-related cancer predisposition (MONDO:0700268)
Inheritance Mode: Autosomal dominant inheritance
UUID: fb382bbb-2346-4169-a45f-4d4247e75156
Approved on: 2026-01-05
Published on: 2026-01-05

HGVS expressions

NM_007294.4(BRCA1):c.101C>T (p.Pro34Leu)
NM_007294.4:c.101C>T
NC_000017.11:g.43115759G>A
CM000679.2:g.43115759G>A
NC_000017.10:g.41267776G>A
CM000679.1:g.41267776G>A
NC_000017.9:g.38521302G>A
NG_005905.2:g.102225C>T
ENST00000354071.8:n.165C>T
ENST00000461574.2:c.101C>T
ENST00000470026.6:c.101C>T
ENST00000473961.6:c.101C>T
ENST00000476777.6:c.101C>T
ENST00000477152.6:c.101C>T
ENST00000478531.6:c.101C>T
ENST00000489037.2:c.101C>T
ENST00000493919.6:c.-8+8258C>T
ENST00000494123.6:c.101C>T
ENST00000497488.2:c.-219+9512C>T
ENST00000618469.2:c.101C>T
ENST00000634433.2:c.101C>T
ENST00000644379.2:c.101C>T
ENST00000644555.2:c.-41C>T
ENST00000652672.2:c.-41C>T
ENST00000484087.6:c.101C>T
ENST00000700182.1:c.101C>T
ENST00000700183.1:c.101C>T
ENST00000700184.1:n.344C>T
ENST00000700185.1:n.220C>T
ENST00000357654.9:c.101C>T
ENST00000471181.7:c.101C>T
ENST00000642945.1:c.101C>T
ENST00000644555.1:c.-41C>T
ENST00000652672.1:c.-41C>T
ENST00000352993.7:c.101C>T
ENST00000354071.7:c.101C>T
ENST00000357654.7:c.101C>T
ENST00000461221.5:c.101C>T
ENST00000461798.5:c.101C>T
ENST00000468300.5:c.101C>T
ENST00000470026.5:c.101C>T
ENST00000471181.6:c.101C>T
ENST00000476777.5:c.101C>T
ENST00000477152.5:c.101C>T
ENST00000478531.5:c.101C>T
ENST00000489037.1:c.101C>T
ENST00000491747.6:c.101C>T
ENST00000492859.5:c.101C>T
ENST00000493795.5:c.-8+8258C>T
ENST00000493919.5:c.-8+8258C>T
ENST00000494123.5:c.101C>T
ENST00000497488.1:c.-219+9512C>T
ENST00000586385.5:c.4+9423C>T
ENST00000591534.5:c.-44+9512C>T
ENST00000591849.5:c.-99+9512C>T
ENST00000634433.1:c.101C>T
NM_007294.3:c.101C>T
NM_007297.3:c.-8+8258C>T
NM_007298.3:c.101C>T
NM_007299.3:c.101C>T
NM_007300.3:c.101C>T
NR_027676.1:n.262C>T
NM_007297.4:c.-8+8258C>T
NM_007299.4:c.101C>T
NM_007300.4:c.101C>T
NR_027676.2:n.303C>T
More

Likely Pathogenic

Met criteria codes 3
PP4_Moderate PS3 PP3
Not Met criteria codes 3
BS1 BA1 PM2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.101C>T variant in BRCA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is present in gnomAD v4.1 but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA1 missense variant is within a key functional domain and a SpliceAI score of 0.01 predicts no impact on splicing (score threshold ≤0.1). The computational predictor BayesDel (noAF) gives a score of 0.45, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35659930, 37168384) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 5.47 (based on Case-Control LR=5.47), within the thresholds for moderate evidence towards pathogenicity (LR ≥4.3 & <18.7) (PP4_Moderate met; PMID: 40413188). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PP4_Moderate).
Met criteria codes
PP4_Moderate
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 5.47 (based on Case-Control LR=5.47), within the thresholds for moderate evidence towards pathogenicity (LR ≥4.3 & <18.7) (PP4_Moderate met; PMID: 40413188).
PS3
Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35659930, 37168384) (PS3 met).
Non-functional PubMed:30209399
PP3
This BRCA1 missense variant is within a key functional domain and a SpliceAI score of 0.01 predicts no impact on splicing (score threshold ≤0.1). The computational predictor BayesDel (noAF) gives a score of 0.45, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change (PP3 met).
Not Met criteria codes
BS1
This variant is present in gnomAD v4.1 but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
BA1
This variant is present in gnomAD v4.1 but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
PM2
This variant is present in gnomAD v4.1 but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
Curation History
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