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

BP1 Strong (benign)

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): missense change outside all ENIGMA-defined BRCA1 functional domains with no predicted splicing impact (SpliceAI max delta 0.01, threshold <=0.1).

2

Overall classification: Uncertain Significance — the single BP1 Strong benign code does not satisfy any ENIGMA Table 3 Likely Benign combination, which requires multiple independent benign evidence types.

Final determination: Under ENIGMA BRCA1/2 VCEP v1.2 Table 3, only one benign-direction code (BP1, Strong) is met and no pathogenic-direction code is met; a single Strong (Benign) code alone does not meet the Likely Benign pathway because that pathway requires multiple independent evidence types, so no Table 3 combination is satisfied and the variant remains 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	N/A	Not applicable: this is a missense substitution (p.Gly1087Ala), not a null variant such as nonsense, frameshift, or canonical splice-site change.	cspec
PS1	Not assessed	Not assessed: no comparator variant producing the same p.Gly1087Ala change through a different nucleotide substitution was identified.	cspec
PS2	N/A	Not applicable: the ENIGMA VCEP excludes de novo evidence because BRCA1/2 cancers are common and its predictive value is uncalibrated.	cspec
PS3	Not assessed	Not assessed: no calibrated functional assay result for p.Gly1087Ala has been published in any VCEP-curated dataset.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PS4	Not assessed	Not assessed: no case-control counts, p-value, odds ratio, or confidence interval for this variant were available.	cspec clinvar
PM1	N/A	Not applicable: the ENIGMA VCEP does not use PM1 for BRCA1, and Gly1087 lies outside all defined functional domains.	cspec
PM2	Not met	Not met: the variant is present in gnomAD v2.1 controls (1/250,540 alleles), failing the required absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no Fanconi anemia phenotype, second BRCA1 variant, or phase information was documented.	cspec
PM4	N/A	Not applicable: this missense substitution does not alter protein length, and the VCEP does not apply PM4 to BRCA1/2.	cspec
PM5	N/A	Not applicable: ENIGMA restricts PM5 to protein-truncating variants, and p.Gly1087Ala is a missense change.	cspec pm5_candidates
PM6	N/A	Not applicable: the ENIGMA VCEP excludes presumed de novo occurrences because their predictive value for BRCA1/2 is uncalibrated.	cspec
PP1	Not assessed	Not assessed: no family pedigree, parental testing, or segregation data were available for this variant.	cspec
PP2	N/A	Not applicable: the ENIGMA VCEP does not use the standalone low-benign-missense-rate PP2 rule for BRCA1.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.015 is below the 0.2 threshold, and the BayesDel pathway applies only within functional domains.	cspec spliceai
PP4	Not assessed	Not assessed: no calibrated multifactorial likelihood ratio for this variant was available.	cspec PMID:31853058 PMID:17924331
PP5	N/A	Not applicable: the variant has no expert-panel ClinVar submissions, and the VCEP does not apply PP5.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 allele frequency 3.99e-06 is far below the 0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD grpmax FAF 1.57e-05 does not reach the BS1 supporting threshold of 2e-05.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying unaffected-individual observations were available to evaluate BS2.	cspec
BS3	Not assessed	Not assessed: no calibrated functional assay evidence supporting a benign effect on p.Gly1087Ala was available.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BS4	Not assessed	Not assessed: no family or segregation data were available to evaluate lack of segregation.	cspec
BP1	Met	Met (Strong): p.Gly1087Ala lies outside all ENIGMA-defined BRCA1 domains, with SpliceAI max delta 0.01 (below the 0.1 threshold).	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA VCEP designates BP2 as not applicable for BRCA1/2.	cspec
BP3	N/A	Not applicable: BP3 applies only to in-frame indels in repeat regions; this is a missense substitution.	cspec
BP4	N/A	Not applicable: BP4 is domain-restricted, and this variant lies outside all BRCA1 domains, so it falls under BP1 instead.	cspec
BP5	Not assessed	Not assessed: no calibrated multifactorial likelihood ratio against pathogenicity was available.	cspec PMID:31853058 PMID:17924331 clinvar
BP6	N/A	Not applicable: no expert-panel ClinVar submission exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to intronic or silent variants; p.Gly1087Ala is a missense change.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.