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

Likely Benign

BP1 strong BP5 supporting

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 at residue 1087, outside all clinically important functional domains, with no predicted splicing impact (SpliceAI max delta 0.015).

2

BP5 (Supporting): clinical-history likelihood ratio of 0.31 from four probands, below the 0.48 supporting threshold.

3

Overall: with only benign-direction criteria applied (BP1_Strong + BP5_Supporting) and no pathogenic-direction evidence, ENIGMA v1.2 Table 3 yields Likely Benign.

Final determination:

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 change (p.Gly1087Ala), not a null variant such as a nonsense, frameshift, or splice-site alteration.	cspec
PS1	Not assessed	Not assessed: no previously classified pathogenic variant at codon 1087 exists to compare, and no splicing impact is predicted (SpliceAI max delta 0.015).	spliceai
PS2	N/A	Not applicable: the ENIGMA specification excludes de novo evidence because BRCA1/2-related cancers are common and de novo predictive capacity is uncalibrated.	cspec vcep_specifications_v1_2_2024_11_18
PS3	Not assessed	Not assessed: no calibrated functional assay result (e.g., saturation genome editing, HDR) is on record for p.Gly1087Ala.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	Not assessed: no case-control study for this exact variant reports an odds ratio with statistical significance.	cspec
PM1	N/A	Not applicable: the ENIGMA BRCA1/2 specification marks PM1 as not applicable; domain evidence is captured through other rules.	cspec
PM2	Not met	Not met: the variant is observed once in gnomAD v2.1 (1/250,540 alleles), so it is not absent from population databases as PM2 requires.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband with a Fanconi anemia phenotype and a second BRCA1 variant was available for assessment.	cspec
PM4	N/A	Not applicable: p.Gly1087Ala is a single-amino-acid substitution causing no protein length change, and ENIGMA marks PM4 not applicable.	cspec
PM5	N/A	Not applicable: ENIGMA restricts PM5 to premature-termination-codon variants, and this is a missense substitution.	cspec pm5_candidates
PM6	N/A	Not applicable: the ENIGMA specification excludes de novo evidence because BRCA1/2-related cancers are common and de novo predictive capacity is uncalibrated.	cspec vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	Not assessed: no co-segregation likelihood ratio is available from the ENIGMA multifactorial data.	cspec vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
PP2	N/A	Not applicable: the ENIGMA BRCA1/2 specification explicitly marks PP2 as not applicable.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.015 is far below the 0.2 splicing-impact threshold, and residue 1087 lies outside all functional domains.	cspec spliceai
PP4	Not met	Not met: the clinical-history likelihood ratio of 0.31 is below the PP4 supporting threshold of 2.08.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	Not applicable: the ENIGMA specification does not use PP5, and ClinVar has no expert-panel submission for this variant.	cspec clinvar
BA1	Not met	Not met: the gnomAD v2.1 allele frequency of 1/250,540 (AF 4.0e-06) is far below the BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: no filtering allele frequency exceeds the BS1 thresholds; the gnomAD v4.1 grpmax FAF of 1.6e-05 is below the supporting lower bound of 2e-05.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no phenotyped individuals carrying a co-occurring pathogenic BRCA1 variant were available, as BS2 requires.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no published functional assay result for this variant exists to demonstrate normal protein function.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	Not assessed: no non-segregation likelihood ratio is available from the ENIGMA multifactorial data.	cspec vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
BP1	Met	Met (Strong): missense at residue 1087, outside all functional domains, with no predicted splicing impact (SpliceAI max delta 0.015, below the 0.1 threshold).	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA1/2 specification explicitly marks BP2 as not applicable.	cspec
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel, and ENIGMA marks BP3 not applicable.	cspec
BP4	N/A	Not applicable: BP4 is restricted to variants inside functional domains, and residue 1087 lies outside all of them.	cspec
BP5	Met	Met (Supporting): clinical-history likelihood ratio of 0.31 from four probands is below the 0.48 supporting threshold.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	Not applicable: the ENIGMA specification does not use BP6, and no expert-panel benign assertion exists in ClinVar.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers silent and intronic variants, and this missense change lacks the required splicing-assay data.

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