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 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!
  • 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.5254G>A (p.Ala1752Thr)

CA003393

96944 (ClinVar)

Gene: BRCA1 (HGNC:672)
Condition: BRCA1-related cancer predisposition (MONDO:0700268)
Inheritance Mode: Autosomal dominant inheritance
UUID: b09c53c0-ad1b-444b-8392-d4530fd13d21
Approved on: 2025-12-03
Published on: 2025-12-02

HGVS expressions

NM_007294.4:c.5254G>A
NM_007294.4(BRCA1):c.5254G>A (p.Ala1752Thr)
NC_000017.11:g.43057075C>T
CM000679.2:g.43057075C>T
NC_000017.10:g.41209092C>T
CM000679.1:g.41209092C>T
NC_000017.9:g.38462618C>T
NG_005905.2:g.160909G>A
ENST00000461574.2:c.5251G>A
ENST00000470026.6:c.5254G>A
ENST00000473961.6:c.5128G>A
ENST00000476777.6:c.5248G>A
ENST00000477152.6:c.5176G>A
ENST00000478531.6:c.1942G>A
ENST00000489037.2:c.5176G>A
ENST00000493919.6:c.1804G>A
ENST00000494123.6:c.5254G>A
ENST00000497488.2:c.4366G>A
ENST00000618469.2:c.5254G>A
ENST00000634433.2:c.5131G>A
ENST00000644379.2:c.5320G>A
ENST00000644555.2:c.1804G>A
ENST00000652672.2:c.5113G>A
ENST00000484087.6:c.1816G>A
ENST00000357654.9:c.5254G>A
ENST00000471181.7:c.5317G>A
ENST00000644379.1:c.1641G>A
ENST00000352993.7:c.1828G>A
ENST00000357654.7:c.5254G>A
ENST00000461221.5:c.*5037G>A
ENST00000468300.5:c.1942G>A
ENST00000471181.6:c.5317G>A
ENST00000491747.6:c.1942G>A
ENST00000493795.5:c.5113G>A
ENST00000586385.5:c.184G>A
ENST00000591534.5:c.727G>A
ENST00000591849.5:c.-98-6885G>A
NM_007294.3:c.5254G>A
NM_007297.3:c.5113G>A
NM_007298.3:c.1942G>A
NM_007299.3:c.1942G>A
NM_007300.3:c.5317G>A
NR_027676.1:n.5390G>A
NM_007297.4:c.5113G>A
NM_007299.4:c.1942G>A
NM_007300.4:c.5317G>A
NR_027676.2:n.5431G>A
More

Uncertain Significance

Met criteria codes 3
BP4 PS3 PM2_Supporting
Not Met criteria codes 2
BP5 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.5254G>A variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1752 (p.(Ala1752Thr)). 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). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 30257991, 38709234) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.1, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (BP4 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.12 (based on Cosegregation LR=1.12), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not 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 (PM2_Supporting, PS3, BP4).
Met criteria codes
BP4
This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.1, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (BP4 met).
PS3
Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 30257991, 38709234) (PS3 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
BP5
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.12 (based on Cosegregation LR=1.12), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor).
PP4
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.12 (based on Cosegregation LR=1.12), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor).
Curation History
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