Variant classification summary

NM_007294.4:c.4189A>G

BRCA1 · NP_009225.1:p.(Arg1397Gly) · NM_007294.4

GRCh37: chr17:41234589 T>C · GRCh38: chr17:43082572 T>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

PM2 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Arg1397Gly)

gnomAD AF

1.2390483612965898e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.4189A>G (p.Arg1397Gly) is a rare missense variant in BRCA1 exon 12, located within the ENIGMA clinically important coiled-coil domain (aa 1391–1424).

2

The variant is absent from gnomAD v2.1 and observed at extremely low frequency in gnomAD v4.1 (2/1,614,142 alleles; grpmax FAF=2.8×10⁻⁷), meeting ENIGMA PM2_Supporting.

3

In silico predictions are indeterminate: REVEL score is 0.594 (elevated), but the ENIGMA-specified BayesDel no-AF score of 0.153 falls between the BP4 threshold (≤0.15) and PP3 threshold (≥0.28), and SpliceAI predicts no splicing impact (max delta=0.04). Neither PP3 nor BP4 is met.

4

No variant-specific functional data, clinical-history likelihood ratios, cosegregation analysis, or case-control data were identified in the ENIGMA VCEP materials or literature reviewed.

5

With only PM2_Supporting met and no other applicable criteria, the evidence is insufficient to classify this variant beyond Uncertain Significance (VUS) under the ENIGMA BRCA1/2 v1.2.0 framework. The combination of a single supporting-level pathogenic criterion does not reach the Likely Pathogenic threshold.

Final determination: Under ENIGMA BRCA1/2 v1.2.0 Table 3 combination rules, a single Supporting-level pathogenic criterion (PM2_Supporting) does not satisfy any Pathogenic or Likely Pathogenic combination threshold, and no benign criteria are met; the variant defaults to 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	NM_007294.4:c.4189A>G is a missense variant (p.Arg1397Gly), not a null variant (nonsense, frameshift, canonical splice ±1,2). ENIGMA PVS1 applies only to null variants per Specifications Table 4.
PS1	Not met	No previously classified pathogenic missense variant at BRCA1 codon Arg1397 was identified in ENIGMA Table 9, Supplementary Tables, or ClinVar expert-reviewed submissions. PS1 requires a known pathogenic variant at the same amino acid position acting via the same mechanism.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	PS2 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
PS3	Not assessed	NM_007294.4:c.4189A>G is not listed in ENIGMA Table 9 (curated functional assay results) or Supplementary Table 4 (full functional assay dataset). No variant-specific functional evidence from calibrated mammalian studies was identified.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control study data with p-value and odds ratio meeting ENIGMA PS4 thresholds (p≤0.05, OR≥4, lower CI excludes 2.0) was identified for this variant.
PS5	N/A	PS5 is not included in the ENIGMA BRCA1/2 cspec v1.2.0 criteria set.	cspec
PM1	N/A	PM1 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
PM2	Met	NM_007294.4:c.4189A>G is absent from gnomAD v2.1 (non-cancer, exome). In gnomAD v4.1, it is observed at extremely low frequency (2/1,614,142 alleles; grpmax FAF=2.8×10⁻⁷), effectively absent from outbred control populations. Meets ENIGMA PM2_Supporting threshold.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA PM5 is repurposed for protein termination codon (PTC) variants only. This is a missense variant (p.Arg1397Gly) and does not qualify. Classic same-residue missense PM5 is not used in the ENIGMA framework.	pm5_candidates
PM6	N/A	PM6 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
PP1	Not assessed	No cosegregation data or quantitative cosegregation likelihood ratio analysis was identified for this variant.
PP2	N/A	PP2 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
PP3	Not met	p.Arg1397Gly lies within the ENIGMA clinically important coiled-coil domain (aa 1391–1424), but BayesDel no-AF score is 0.153, below the ENIGMA PP3 threshold of ≥0.28. SpliceAI max delta is 0.04, well below the 0.2 threshold. No predicted pathogenic impact by ENIGMA bioinformatic criteria.	bayesdel revel spliceai cspec
PP4	Not assessed	NM_007294.4:c.4189A>G (p.Arg1397Gly) is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. No phenotype likelihood ratio can be computed. Also absent from the Parsons et al. 2019 (HUMU-40-1557-s001) multifactorial dataset.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
PP5	N/A	PP5 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
BA1	Not met	The grpmax filter allele frequency in gnomAD v4.1 is 2.8×10⁻⁷, far below the ENIGMA BA1 threshold of FAF>0.001 (0.1%). The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The grpmax filter allele frequency is 2.8×10⁻⁷, below the ENIGMA BS1_Supporting threshold of FAF>0.00002 (0.002%). The variant is too rare to meet any BS1 strength level.	gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA BS2 requires proband-level observation in the absence of Fanconi anemia phenotype features (Specifications Table 8). No proband-level data for this variant were available in the case materials.
BS3	Not assessed	NM_007294.4:c.4189A>G is not listed in ENIGMA Table 9 (curated functional assay results) or Supplementary Table 4. No calibrated functional evidence showing no damaging effect was identified for this variant.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative cosegregation analysis showing lack of segregation was identified for this variant.
BP1	Not met	p.Arg1397Gly is located within the ENIGMA clinically important coiled-coil domain (aa 1391–1424). BP1_Strong requires the missense variant to be outside a clinically important functional domain and have no predicted splicing impact (SpliceAI≤0.1). The variant fails the domain location requirement.	cspec
BP2	N/A	BP2 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
BP4	Not met	p.Arg1397Gly lies within the coiled-coil functional domain, but BayesDel no-AF score is 0.153, exceeding the ENIGMA BP4 threshold of ≤0.15. Although SpliceAI max delta is 0.04 (≤0.1, no splicing predicted), the BayesDel threshold is not met. Both conditions must be satisfied for BP4 in a missense variant inside a functional domain.	bayesdel spliceai cspec
BP5	Not assessed	NM_007294.4:c.4189A>G is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. No phenotype LR toward benignity can be computed.	vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	BP6 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0.	cspec
BP7	N/A	NM_007294.4:c.4189A>G is a missense variant inside the coiled-coil functional domain (aa 1391–1424). ENIGMA BP7_Supporting applies only to silent variants inside a functional domain or intronic variants at or beyond +7/−21, both contingent on BP4 being met (which it is not). BP7_Strong (RNA) requires BS3 for missense variants inside a functional domain, which is not available.	cspec

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