The BRCA1 c.32T>G (p.(Val11Gly)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA with additional conflicting submissions.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases consistent with PM2_Supporting.2 In calibrated functional data, this variant showed complete functional impact with loss of function and was summarized by the ENIGMA BRCA1 specification as meeting PS3_Strong.3 This missense change is located in the BRCA1 RING domain, with BayesDel no-AF 0.325211 above the ENIGMA PP3 threshold of 0.28 and REVEL 0.753, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.00; these findings support PP3 and do not support BP4.4
BRCA1
Final classification
Likely Pathogenic
BRCA1 c.32T>G · p.Val11Gly
BRCA1
The BRCA1 c.32T>G (p.(Val11Gly)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA with additional conflicting submissions.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 adapted ACMG/AMP criteria-combination rules)
Classification rationale
PS3PM2PP3PP5
Likely Pathogenic
BRCA1 c.32T>G
PS3 + PM2 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗
4
cspec ↗bayesdelrevelspliceai ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 245973)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.753. BayesDel score = 0.325211.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
18493658 ↗
Re-engineering a split-GFP reassembly screen to examine RING-domain interactions between BARD1 and BRCA1 mutants observed in cancer patients.
ONCOKB
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
30219179 ↗
A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function.
CLINVAR
30702160 ↗
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.
CLINVAR
31853058 ↗
Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.
CLINVAR
31911673 ↗
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
CLINVAR
32377563 ↗
Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR