Variant classification summary

NM_007294.4:c.3270A>G

BRCA1 · NP_009225.1:p.(Gln1090=) · NM_007294.4

GRCh37: chr17:41244278 T>C · GRCh38: chr17:43092261 T>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

BP1 strong BP6 supporting benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Gln1090=)

gnomAD AF

1.4253171020700562e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BP1 Strong is supported by synonymous Q1090 being outside ENIGMA functional domains with SpliceAI maximum delta 0.002.

2

Likely Benign: BP6 Supporting is supported by the exact-variant ClinVar expert-panel Likely benign classification.

Final determination: Under ENIGMA Table 3, one Strong benign criterion plus one Supporting benign criterion, specifically BP1 Strong and BP6 Supporting benign, yields Likely Benign.

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: the synonymous p.(Gln1090=) substitution is not a PVS1 null-variant class, and SpliceAI max delta is 0.002, below 0.2.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS1	N/A	Not applicable: the variant is synonymous (p.Gln1090=), whereas ENIGMA PS1 requires a same-amino-acid missense or precisely matched splice effect.	cspec spliceai
PS2	N/A	Not applicable: the ENIGMA specification prohibits PS2 because de novo occurrences have no calibrated predictive capacity for BRCA1/2-related cancers.	cspec vcep_specifications_v1_2_2024_11_18
PS3	Not assessed	Not assessed: no variant-specific calibrated protein or combined mRNA–protein functional assay result was found for c.3270A>G (p.Gln1090=).	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 exact-variant case-control odds ratio, p-value, or confidence interval is available to evaluate the ENIGMA PS4 thresholds.	cspec
PM1	N/A	Not applicable: ENIGMA does not use PM1, and residue Q1090 lies outside the specified BRCA1 functional domains.	cspec
PM2	Not met	Not met: the variant is present with 2 alleles in both governing non-cancer datasets, rather than absent as required for PM2.	cspec gnomad_v2
PM3	Not assessed	Not assessed: no Fanconi-anemia phenotype, co-occurring pathogenic BRCA1 variant, or phase information is documented for c.3270A>G.	cspec PMID:16267036
PM4	N/A	Not applicable: p.(Gln1090=) causes no protein length change, whereas ENIGMA PM4 covers only in-frame length changes or stop-loss variants.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM5	N/A	Not applicable: the variant is synonymous, while ENIGMA PM5 is not used for ordinary missense comparisons and its repurposed form requires a PVS1 protein-termination variant.	cspec
PM6	N/A	Not applicable: the ENIGMA specification prohibits PM6 because de novo predictive capacity is uncalibrated for common BRCA1/2-related cancers.	cspec vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	Not assessed: no affected-relative segregation data or quantitative LR is available to compare with the PP1 Supporting threshold of 2.08:1.	cspec vcep_specifications_v1_2_2024_11_18 PMID:17924331
PP2	N/A	Not applicable: ENIGMA does not use PP2 for BRCA1, and this variant is synonymous rather than missense.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.002 is below the ENIGMA PP3 threshold of >=0.2 for predicted splicing.	cspec spliceai
PP4	Not assessed	Not assessed: no exact-variant combined multifactorial likelihood ratio is available for comparison with the ENIGMA PP4 threshold of >=2.08:1.	cspec PMID:31853058 PMID:17924331
PP5	Not met	Not met: exact-variant ClinVar expert-panel classification is Likely benign, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: maximum non-cancer filter allele frequency was 4.88e-06, below the ENIGMA BA1 threshold of >0.001.	cspec gnomad_v2
BS1	Not met	Not met: maximum non-cancer filter allele frequency was 4.88e-06, below the ENIGMA BS1 Supporting threshold of >0.00002.	cspec gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but ENIGMA excludes population observations and no qualifying phenotyped adult was documented.	cspec gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific calibrated benign protein or combined mRNA–protein assay result was found for c.3270A>G (p.Gln1090=).	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-segregating affected relatives or quantitative LR is available to compare with the BS4 Supporting threshold of 0.48.	cspec vcep_specifications_v1_2_2024_11_18 PMID:17924331
BP1	Met	Met, strong: synonymous Q1090 is outside ENIGMA BRCA1 domains and SpliceAI max delta 0.002 is below the <=0.1 BP1 threshold.	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA1 specification explicitly prohibits BP2 except as part of BS2, which is outside this criterion assessment.	cspec
BP3	N/A	Not applicable: the synonymous p.(Gln1090=) substitution is not an in-frame insertion/deletion, the variant class required by ENIGMA BP3.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4	N/A	Not applicable: BP4 is restricted here to missense or splice-region/intronic variants, whereas c.3270A>G is synonymous.	cspec
BP5	Not assessed	Not assessed: no exact-variant multifactorial likelihood ratio is available to test against the BP5 Supporting threshold of <=0.48:1.	cspec PMID:31853058 PMID:17924331
BP6	Met	Met, Supporting: exact-variant ClinVar expert-panel classification is Likely benign for variation 187419.	clinvar
BP7	N/A	Not applicable: p.Gln1090 lies outside ENIGMA BRCA1 functional domains, so BP7's domain-and-BP4 condition is not satisfied.	cspec spliceai

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