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
Final classification
Likely Pathogenic
PS3PM2PP3PP5
BRCA1
c.32T>G
p.Val11Gly
This variant
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 ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In a calibrated functional study summarized by the ENIGMA BRCA1 specification, this variant showed loss of function with complete functional impact and behaved similarly to pathogenic control variants, supporting a damaging effect on BRCA1 protein function.
Table 9: c.32T>G p.(Val11Gly) assigned PS3 StrongST4: Functional impact - completeLOF
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength in the reviewed evidence.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PP3
supporting
Pathogenic
This missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain. BayesDel no-AF is 0.325211, which is above the ENIGMA PP3 threshold of 0.28, and REVEL is 0.753, supporting a damaging protein effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
RING domain location at codon 11BayesDel no-AF 0.325211REVEL 0.753
Assessed · not applied
· 7 not met · 6 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic comparator or same-splicing-impact pathogenic comparator was identified in the reviewed materials, so PS1 was not established.
PS4
No case-control study or quantified enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls, so PS4 was not established.
PM3
No evidence was identified that this variant was observed with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not established.
PP1
No segregation data were identified for this variant, so PP1 was not established.
PP4
The BRCA1 clinical-history likelihood ratio for this variant is 1.0618 based on 1 proband, which is below the ENIGMA PP4 supporting threshold of 2.08.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the ENIGMA BA1 stand-alone threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the ENIGMA BS1 population thresholds above 0.002% or 0.01%.
BS2
No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2, so BS2 was not established.
BS3
Available functional evidence does not show a normal or non-damaging effect.
BS4
No non-segregation data were identified for this variant, so BS4 was not established.
BP1
This missense variant is located at codon 11 within the BRCA1 RING domain (aa 2-101), so it is not outside a clinically important functional domain.
BP4
Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, BP4 is not met because this missense variant is in the BRCA1 RING domain and BayesDel no-AF is 0.325211, which is above the benign threshold of 0.15 rather than at or below it.
BP5
The BRCA1 clinical-history likelihood ratio for this variant is 1.0618 based on 1 proband, which is above the ENIGMA BP5 supporting threshold of 0.48.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
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. 8 further PMIDs triaged but not cited — see Sources & references.
Accurate classification of BRCA1 variants with saturation genome editing.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links
Triaged references · 8 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