Variant classification summary

NM_007294.4:c.3260G>C

BRCA1 · NP_009225.1:p.(Gly1087Ala) · NM_007294.4

GRCh37: chr17:41244288 C>G · GRCh38: chr17:43092271 C>G

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

BP1 strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Gly1087Ala)

gnomAD AF

1.7971879585927895e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 (Strong): p.Gly1087Ala is a missense change outside all ENIGMA clinically important BRCA1 domains (RING, coiled-coil, BRCT), with SpliceAI max delta 0.015 below the 0.1 threshold.

2

Overall classification: VUS - the lone BP1_Strong meets neither the ENIGMA Benign rule (BA1 or >=2 Strong) nor the Likely Benign rule (1 Strong plus additional evidence), so the variant defaults to Uncertain Significance.

Final determination: Under ENIGMA BRCA1/2 v1.2 Table 3, no Pathogenic/Likely Pathogenic combination (none of PVS1, PS, PM, or PP met) and no Benign/Likely Benign combination (only 1 Strong benign criterion, BP1_Strong, which requires a second qualifying benign criterion or evidence type for Likely Benign and >=2 Strong or BA1 stand-alone for Benign) is satisfied, so the variant is classified as Uncertain Significance.

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	Not met	Not met: p.(Gly1087Ala) is a missense substitution with an unchanged predicted protein endpoint, not a null variant.	cspec
PS1	Not assessed	Not assessed: no documented pathogenic BRCA1 variant producing the same amino-acid change was available for comparison.	cspec spliceai
PS2	N/A	Not applicable: the ENIGMA BRCA1/2 specification excludes de novo occurrence evidence because these cancers are relatively common.	cspec
PS3	Not assessed	Not assessed: no calibrated functional assay or published study of this exact variant was available.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	Not assessed: no case-control data for this exact variant were available.	cspec vcep_humu_40_1557_s001
PM1	N/A	Not applicable: p.Gly1087Ala lies outside the BRCA1 clinically important domains (RING, coiled-coil, BRCT), and ENIGMA does not apply PM1.	cspec
PM2	Not met	Not met: the variant is observed in population controls (gnomAD v2.1: 1/250,540 alleles), where PM2 requires absence.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no patient phenotype, second BRCA1 variant, or phase data were available to evaluate a Fanconi anemia presentation.	cspec vcep_humu_40_1557_s001
PM4	N/A	Not applicable: ENIGMA excludes PM4, and this is a single-residue substitution with no protein-length change.	cspec
PM5	N/A	Not applicable: ENIGMA restricts PM5 to protein-truncating variants, and p.Gly1087Ala is a missense substitution.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA specification excludes PM6 (de novo evidence) for BRCA1/2.	cspec
PP1	Not assessed	Not assessed: no quantitative co-segregation data (segregation likelihood ratio or affected-relative genotypes) were available.	cspec vcep_humu_40_1557_s001
PP2	N/A	Not applicable: the ENIGMA BRCA1/2 specification explicitly excludes PP2.	cspec
PP3	Not met	Not met: p.Gly1087Ala lies outside the clinically important BRCA1 domains, and its SpliceAI max delta of 0.015 is below the 0.2 threshold.	cspec spliceai bayesdel
PP4	Not met	Not met: the combined multifactorial likelihood ratio is 0.31, below the PP4 thresholds.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	Not applicable: ENIGMA excludes PP5, and ClinVar holds no expert-panel submissions for this variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 allele frequency is 3.99e-06, far below the >0.001 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: current gnomAD v4.1 grpmax FAF is 1.567e-05, below the BS1 supporting threshold of 2e-05. Flagged for human review: an older one-count record (max MAF 6.7e-05) sits within the supporting range, and upholding it would make the variant Likely Benign.	cspec gnomad_v2 gnomad_v4 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BS2	Not assessed	Not assessed: no patient-level data (phenotype, chromosome-breakage result, biallelic genotype) were available to assess recessive-disease features.	cspec
BS3	Not assessed	Not assessed: no functional studies demonstrating a benign effect of this exact variant were available.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	Not assessed: no quantitative segregation data (non-segregating affected relatives) were available.	cspec vcep_humu_40_1557_s001
BP1	Met	Met (Strong): p.Gly1087Ala is a missense change outside all ENIGMA clinically important BRCA1 domains, with SpliceAI max delta 0.015 below the 0.1 threshold.	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA1/2 specification designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: ENIGMA designates BP3 as not applicable, and this missense is not an in-frame indel.	cspec
BP4	Not met	Not met: although BayesDel (-0.18) and SpliceAI (0.015) pass their cutoffs, p.Gly1087Ala lies outside the BRCA1 domains BP4 requires.	cspec spliceai bayesdel
BP5	Not met	Not met: the combined multifactorial likelihood ratio of 0.31 does not meet the ENIGMA BP5 supporting requirement.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	Not applicable: ENIGMA excludes BP6, and no expert-panel classifications exist for this variant.	cspec clinvar
BP7	Not assessed	Not assessed: no variant-specific RNA assay was available, and BP7 otherwise applies only to synonymous or intronic variants.	cspec spliceai

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