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.5075A>T (p.Asp1692Val)

CA003216

55383 (ClinVar)

Gene: BRCA1
Condition: BRCA1-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 93d8bd27-96bf-44f5-9d60-9dec6ff27ac9
Approved on: 2025-05-23
Published on: 2025-05-23

HGVS expressions

NM_007294.4:c.5075A>T
NM_007294.4(BRCA1):c.5075A>T (p.Asp1692Val)
NC_000017.11:g.43063951T>A
CM000679.2:g.43063951T>A
NC_000017.10:g.41215968T>A
CM000679.1:g.41215968T>A
NC_000017.9:g.38469494T>A
NG_005905.2:g.154033A>T
ENST00000461574.2:c.5072A>T
ENST00000470026.6:c.5075A>T
ENST00000473961.6:c.4949A>T
ENST00000476777.6:c.5069A>T
ENST00000477152.6:c.4997A>T
ENST00000478531.6:c.1763A>T
ENST00000489037.2:c.4997A>T
ENST00000493919.6:c.1625A>T
ENST00000494123.6:c.5075A>T
ENST00000497488.2:c.4187A>T
ENST00000618469.2:c.5075A>T
ENST00000634433.2:c.4952A>T
ENST00000644379.2:c.5141A>T
ENST00000644555.2:c.1625A>T
ENST00000652672.2:c.4934A>T
ENST00000484087.6:c.1637A>T
ENST00000357654.9:c.5075A>T
ENST00000471181.7:c.5138A>T
ENST00000644379.1:c.1462A>T
ENST00000352993.7:c.1649A>T
ENST00000357654.7:c.5075A>T
ENST00000461221.5:c.*4858A>T
ENST00000468300.5:c.1763A>T
ENST00000471181.6:c.5138A>T
ENST00000478531.5:c.1763A>T
ENST00000484087.5:c.1388A>T
ENST00000491747.6:c.1763A>T
ENST00000493795.5:c.4934A>T
ENST00000493919.5:c.1625A>T
ENST00000586385.5:c.5A>T
ENST00000591534.5:c.548A>T
ENST00000591849.5:c.-98-13761A>T
NM_007294.3:c.5075A>T
NM_007297.3:c.4934A>T
NM_007298.3:c.1763A>T
NM_007299.3:c.1763A>T
NM_007300.3:c.5138A>T
NR_027676.1:n.5211A>T
NM_007297.4:c.4934A>T
NM_007299.4:c.1763A>T
NM_007300.4:c.5138A>T
NR_027676.2:n.5252A>T
More

Likely Pathogenic

Met criteria codes 4
PP4_Moderate PS3 PP3 PM2_Supporting
Not Met criteria codes 3
BP4 BP1 PS1

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.5075A>T variant in BRCA1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1692 (p.Asp1692Val). 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 0.32, predicting an impact on splicing (score threshold ≥0.2) (PP3 met). Missense variant predicted to alter splicing, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 15.2 (based on Family History LR=15.2), within the thresholds for moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID, 3185305). 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, PS3, PP4_Moderate).
Met criteria codes
PP4_Moderate
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 15.2 (based on Family History LR=15.2), within the thresholds for moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID, 3185305]).
PS3
Missense variant predicted to alter splicing, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit function similar to pathogenic control variants (PMID:30209399) (PS3 met).
PP3
This BRCA1 missense variant has a SpliceAI score of 0.32, predicting an impact on splicing (score threshold ≥0.2) (PP3 met).
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).
Not Met criteria codes
BP4
This BRCA1 missense variant has a SpliceAI score of 0.32, predicting an impact on splicing (score threshold ≥0.2) (PP3 met).
BP1
This BRCA1 missense variant has a SpliceAI score of 0.32, predicting an impact on splicing (score threshold ≥0.2) (PP3 met).
PS1
VUA did not have a higher spliceAI score compared to the -1/2 variants. VUA had higher acceptor loss compared to c.5076T>A (0.31) and c.5075A>C (0.20) - both of those are LP in ClinVar but not yet reviewed by VCEP; score is lower than c.5074G>A (0.73 donor loss) which is path per VCEP.
Curation History
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