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.5425G>T (p.Val1809Phe)

CA003588

55573 (ClinVar)

Gene: BRCA1 (HGNC:672)
Condition: BRCA1-related cancer predisposition (MONDO:0700268)
Inheritance Mode: Autosomal dominant inheritance
UUID: 92dbefd2-5679-4694-be89-56cf41771cff
Approved on: 2026-01-15
Published on: 2026-01-15

HGVS expressions

NM_007294.4:c.5425G>T
NM_007294.4(BRCA1):c.5425G>T (p.Val1809Phe)
NC_000017.11:g.43047685C>A
CM000679.2:g.43047685C>A
NC_000017.10:g.41199702C>A
CM000679.1:g.41199702C>A
NC_000017.9:g.38453228C>A
NG_005905.2:g.170299G>T
ENST00000461574.2:c.5422G>T
ENST00000470026.6:c.5425G>T
ENST00000473961.6:c.5299G>T
ENST00000476777.6:c.5419G>T
ENST00000477152.6:c.5347G>T
ENST00000478531.6:c.2113G>T
ENST00000489037.2:c.5347G>T
ENST00000493919.6:c.1975G>T
ENST00000494123.6:c.5425G>T
ENST00000497488.2:c.4537G>T
ENST00000618469.2:c.5425G>T
ENST00000634433.2:c.5302G>T
ENST00000644379.2:c.5491G>T
ENST00000644555.2:c.1975G>T
ENST00000652672.2:c.5284G>T
ENST00000484087.6:c.1987G>T
ENST00000700081.1:n.1308G>T
ENST00000700082.1:n.789G>T
ENST00000357654.9:c.5425G>T
ENST00000471181.7:c.5488G>T
ENST00000644379.1:c.1812G>T
ENST00000352993.7:c.1999G>T
ENST00000357654.7:c.5425G>T
ENST00000461221.5:c.*5208G>T
ENST00000468300.5:c.2039G>T
ENST00000471181.6:c.5488G>T
ENST00000491747.6:c.2113G>T
ENST00000493795.5:c.5284G>T
ENST00000586385.5:c.355G>T
ENST00000591534.5:c.898G>T
ENST00000591849.5:c.124G>T
NM_007294.3:c.5425G>T
NM_007297.3:c.5284G>T
NM_007298.3:c.2113G>T
NM_007299.3:c.2039G>T
NM_007300.3:c.5488G>T
NR_027676.1:n.5561G>T
NM_007297.4:c.5284G>T
NM_007299.4:c.2039G>T
NM_007300.4:c.5488G>T
NR_027676.2:n.5602G>T
More

Likely Pathogenic

Met criteria codes 3
PP1_Strong PM2_Supporting PS3
Not Met criteria codes 6
BP4 BP1 BP5 BP7 PP4 PP3

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.5425G>T variant in BRCA1 is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 1809 (p.(Val1809Phe)). 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 two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:32546644, 38709234) (PS3 met). mRNA experimental analysis indicates no impact on splicing (PMID: 32123317) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.144, below the recommended threshold of 0.15 for no predicted impact on BRCA1 function via protein change. However, the SpliceAI score of 0.14 indicates an unclear predicted impact on splicing (score range 0.10-0.20) (no bioinformatic code is applied). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.8 (Co-occurrence LR=1.18; Family History LR=0.68), 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). Cosegregation analysis of 2 families carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 23.66 (14.17 and 1.67, applied as LR), within the thresholds for strong pathogenic evidence (LR ≥18.7 & <350) (PP1_Strong met; PMID:15689452, Internal lab contributor). 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, PS3, PP1_Strong).
Met criteria codes
PP1_Strong
Cosegregation analysis of 2 families carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 23.66 (14.17 and 1.67, applied as LR), within the thresholds for strong pathogenic evidence (LR ≥18.7 & <350) (PP1_Strong met; PMID:15689452, Internal lab contributor).
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).
PS3
Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:32546644, 38709234) (PS3 met).
Not Met criteria codes
BP4
This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.144, below the recommended threshold of 0.15 for no predicted impact on BRCA1 function via protein change. However, the SpliceAI score of 0.14 indicates an unclear predicted impact on splicing (score range 0.10-0.20) (no bioinformatic code is applied).
BP1
This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.144, below the recommended threshold of 0.15 for no predicted impact on BRCA1 function via protein change. However, the SpliceAI score of 0.14 indicates an unclear predicted impact on splicing (score range 0.10-0.20) (no bioinformatic code is applied).
BP5
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.8 (Co-occurrence LR=1.18; Family History LR=0.68), 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).
BP7
mRNA experimental analysis indicates no impact on splicing (PMID: 32123317) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met).
PP4
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.8 (Co-occurrence LR=1.18; Family History LR=0.68), 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).
PP3
This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.144, below the recommended threshold of 0.15 for no predicted impact on BRCA1 function via protein change. However, the SpliceAI score of 0.14 indicates an unclear predicted impact on splicing (score range 0.10-0.20) (no bioinformatic code is applied).
Curation History
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