Variant classification summary

NM_007294.3:c.32T>G

BRCA1 · NP_009225.1:p.(Val11Gly) · NM_007294.3

GRCh37: chr17:41276082 A>C · GRCh38: chr17:43124065 A>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

Likely Pathogenic

PS3_Strong PM2_Supporting PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Val11Gly)

gnomAD AF

ClinVar

Likely Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases consistent with PM2_Supporting.

3

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.

4

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.

Final determination: Likely pathogenic based on 1 Strong and 3 Supporting pathogenic criteria under the ENIGMA BRCA1/2 Table 3 criteria-combination rules.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is a missense substitution, p.(Val11Gly), and does not fall into the BRCA1 null-variant categories used for PVS1 such as nonsense, frameshift, initiation codon, or canonical ±1,2 splice-site change.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No same-amino-acid pathogenic comparator or same-splicing-impact pathogenic comparator was identified in the reviewed materials, so PS1 was not established.	cspec
PS2	N/A	This criterion is not used in the ENIGMA BRCA1 framework for this review.	cspec
PS3	Met	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.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399
PS4	Not assessed	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.	cspec
PM1	N/A	PM1 is not applied in the ENIGMA BRCA1/2 specification.	cspec
PM2	Met	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.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	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.	cspec
PM4	N/A	PM4 is not applied in the ENIGMA BRCA1/2 specification.	cspec
PM5	N/A	For BRCA1, PM5 is repurposed for protein-truncating variants in eligible exons rather than classic same-residue missense logic. This variant is a missense substitution, so PM5 does not apply.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not used in the ENIGMA BRCA1 framework for this review.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not established.	cspec
PP2	N/A	PP2 is not applied in the ENIGMA BRCA1/2 specification.	cspec
PP3	Met	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.	cspec bayesdel revel spliceai
PP4	Not met	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. This value is in the neutral zone and does not support PP4.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	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%.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	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.	cspec
BS3	Not met	Available functional evidence does not show a normal or non-damaging effect. Instead, calibrated functional data show complete loss of function, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not established.	cspec
BP1	Not met	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. BP1_Strong therefore does not apply.	cspec spliceai
BP2	N/A	BP2 is not applied in the ENIGMA BRCA1/2 specification.	cspec
BP3	N/A	BP3 is not applied in the ENIGMA BRCA1/2 specification.	cspec
BP4	Not met	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. REVEL is also elevated at 0.753.	cspec bayesdel revel spliceai
BP5	Not met	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. This value is in the neutral zone and does not support BP5.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not applied in the ENIGMA BRCA1/2 specification.	cspec
BP7	N/A	BP7 in this framework is used for silent or intronic variants, or RNA evidence contexts, and does not apply to this missense substitution.	cspec

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