Variant classification summary

NM_007294.4:c.5057A>G

BRCA1 · NP_009225.1:p.(His1686Arg) · NM_007294.4

GRCh37: chr17:41219642 T>C · GRCh38: chr17:43067625 T>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Pathogenic

PS3 Strong PM2 Supporting PP3 Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(His1686Arg)

gnomAD AF

1.2405608823861443e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant in BRCA1 exon 16, located within the BRCT repeat domain (aa 1650-1857), a clinically important functional domain critical for BRCA1 tumor suppressor activity.

2

The variant meets PS3_Strong per ENIGMA Specifications Table 9, based on three calibrated functional studies (Findlay 2018 PMID:30209399; Petitalot 2019 PMID:30257991; Bouwman 2020 PMID:32546644) that demonstrate protein function similar to pathogenic control variants, with complete functional impact (Loss-of-Function) confirmed in the ST4 functional assay dataset.

3

The variant meets PP3_Supporting: it is a missense substitution within the BRCT clinically important functional domain with a BayesDel no-AF score of 0.378 (>=0.28 threshold), predicting deleterious impact via protein change. REVEL score is 0.905. SpliceAI max delta is 0.15, indicating no significant splicing impact.

4

The variant meets PM2_Supporting: it is absent from gnomAD v2.1 (non-cancer, exome only) and present at ultra-rare frequency in gnomAD v4.1 (2/1,612,174 alleles; grpmax FAF=2.8e-07). It is absent from gnomAD-Canada v1.0.

5

PP4 could not be applied: the clinical-history likelihood ratio is LR=1.42 (1 proband, Li et al. 2020 PMID:31853058), which falls in the ENIGMA neutral zone (0.48-2.08) and provides insufficient evidence in either direction.

6

The variant does not meet PVS1 (missense, not a null variant), PS1 (no different nucleotide to same amino acid comparator), PS4 (no case-control study), PP1 (no co-segregation data), BA1/BS1 (frequency too low), BS2 (no healthy adult data), BS3 (functional evidence shows damaging effect), BS4 (no lack-of-segregation data), BP1 (inside functional domain), BP4 (BayesDel >0.15, SpliceAI >0.1), BP5 (LR neutral zone), or BP7 (damaging functional effect).

Final determination: Per ENIGMA BRCA1/BRCA2 VCEP v1.2.0 Table 3, 1 Strong criterion (PS3) plus 2 Supporting criteria (PM2, PP3) meets the Likely Pathogenic combination rule: 1 Strong + ≥2 Supporting → Likely Pathogenic.

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	NM_007294.4:c.5057A>G is a missense variant (p.His1686Arg) in BRCA1 exon 16. PVS1 applies only to null variants (nonsense, frameshift, canonical +/-1,2 splice site, initiation codon, or exon deletion). This variant does not fall into any of those categories and the generic PVS1 framework is not applicable per ENIGMA VCEP v1.2.0.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No different nucleotide change at codon 1686 producing the same amino acid substitution (His1686Arg) has been classified as pathogenic. A single nucleotide change from CAC (His) to CGC (Arg) at c.5057A>G is the only single-nucleotide path to His1686Arg in the standard genetic code. No comparator variant meeting PS1 criteria was identified.
PS2	N/A	PS2 (de novo) is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
PS3	Met	Per ENIGMA Specifications Table 9, NM_007294.4:c.5057A>G (p.His1686Arg) is assigned PS3_Strong based on three calibrated functional studies that demonstrate protein function similar to pathogenic control variants: Findlay 2018 (PMID:30209399) saturation genome editing — classified as Loss-of-Function; Petitalot 2019 (PMID:30257991) — classified as 3P (pathogenic); and Bouwman 2020 (PMID:32546644) — classified as Deleterious. The variant shows complete functional impact (LOF, score -0.447) in the ST4 functional assay dataset and is annotated as LossOfFunction in ST13 with three supporting calibrated studies. SpliceAI max delta = 0.15 indicates no predicted splicing effect, confirming the functional defect is mediated at the protein level.	vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not met	No case-control study demonstrating significantly increased prevalence of NM_007294.4:c.5057A>G in affected individuals versus controls (p-value <= 0.05 and OR >= 4, lower CI excluding 2.0) was identified. The variant is reported in ClinVar as Likely pathogenic/Pathogenic by multiple clinical laboratories, but this reflects aggregate clinical observations rather than a formal case-control study meeting ENIGMA PS4 evidentiary thresholds.	clinvar
PS5	N/A	PS5 is not included in the ENIGMA BRCA1/BRCA2 VCEP v1.2.0 criteria. The closest criterion, PP5 (reputable source recently reports variant as pathogenic), is designated as Not Applicable in the ENIGMA specification.	cspec
PM1	N/A	PM1 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
PM2	Met	NM_007294.4:c.5057A>G is absent from gnomAD v2.1 (non-cancer, exome only subset), meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls. In gnomAD v4.1, the variant is present at ultra-rare frequency (2/1,612,174 alleles; grpmax FAF=2.8e-07; highest in European non-Finnish at 2/1,178,240). The variant is also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 in the ENIGMA BRCA1/BRCA2 specification is repurposed for protein termination codon (PTC) variants (PM5_PTC) — applied to PTC variants in exons where a different proven pathogenic PTC variant has been observed. NM_007294.4:c.5057A>G is a missense variant (p.His1686Arg), not a PTC variant. Classic same-residue missense PM5 is not used in the ENIGMA framework for BRCA1.	pm5_candidates cspec
PM6	N/A	PM6 (de novo) is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
PP1	Not met	No co-segregation data are available for NM_007294.4:c.5057A>G. A quantitative co-segregation analysis (LR >= 2.08 for PP1_Supporting) has not been performed for this variant.
PP2	N/A	PP2 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
PP3	Met	NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant located within the BRCT repeat domain (aa 1650-1857), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.378, which exceeds the ENIGMA PP3 threshold of >=0.28 for predicted impact via protein change. REVEL score is 0.905, consistent with a deleterious prediction. SpliceAI max delta score is 0.15 (<0.2), indicating no significant predicted splicing impact.	bayesdel revel spliceai cspec vcep_supplementarytables_v1_2_2024_11_18
PP4	Not met	The clinical-history likelihood ratio for NM_007294.4:c.5057A>G is LR = 1.42 (based on 1 proband, from Li et al. 2020 PMID:31853058). This falls within the ENIGMA neutral zone (>0.48 and <2.08), where neither PP4 nor BP5 can be applied. The evidence is insufficient to support pathogenicity or benignity from personal/family history data.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	PP5 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
BA1	Not met	The grpmax filter allele frequency (FAF) for NM_007294.4:c.5057A>G in gnomAD v4.1 is 2.8e-07 (0.000028%), which is far below the ENIGMA BA1 threshold of FAF > 0.1% (0.001). The variant is absent from gnomAD v2.1.	gnomad_v2 gnomad_v4
BS1	Not met	The grpmax FAF of 2.8e-07 is below both the ENIGMA BS1_Strong threshold (FAF > 0.0001, i.e., >0.01%) and the BS1_Supporting threshold (FAF > 0.00002 and <= 0.0001, i.e., >0.002% and <=0.01%). The variant does not meet any BS1 strength level.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available for observation of NM_007294.4:c.5057A>G in healthy adults without features of Fanconi Anemia. BS2 requires specific proband-level data per ENIGMA Specifications Table 8 point system, which has not been assembled for this variant.
BS3	Not met	ENIGMA Specifications Table 9 assigns PS3_Strong, not BS3, for NM_007294.4:c.5057A>G. Three calibrated functional studies demonstrate a damaging effect on protein function (Loss-of-Function). No well-established functional studies show no damaging effect; the evidence direction is uniformly pathogenic.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not met	No quantitative co-segregation analysis demonstrating lack of segregation with disease (LR <= 0.48 for BS4_Supporting) has been performed for NM_007294.4:c.5057A>G.
BP1	Not met	NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant located within the BRCT repeat domain (aa 1650-1857), which is a clinically important functional domain per ENIGMA specifications. BP1_Strong requires the variant to be located OUTSIDE a clinically important functional domain with no predicted splicing (SpliceAI <= 0.1). Since this variant is inside the BRCT domain, BP1 cannot be applied.	cspec
BP2	N/A	BP2 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
BP4	Not met	BP4_Supporting requires: (a) missense variant inside a clinically important functional domain, AND (b) BayesDel no-AF score <= 0.15, AND (c) SpliceAI <= 0.1. While this variant is inside the BRCT domain, the BayesDel score is 0.378 (>0.15 threshold) and SpliceAI max delta is 0.15 (>0.1 threshold). Neither computational criterion for BP4 is met.	bayesdel spliceai cspec
BP5	Not met	The clinical-history likelihood ratio for NM_007294.4:c.5057A>G is LR = 1.42 (based on 1 proband). This falls within the ENIGMA neutral zone (>0.48 and <2.08). BP5 cannot be applied; the evidence neither supports nor refutes pathogenicity from personal/family history data.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	BP6 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0.	cspec
BP7	Not met	NM_007294.4:c.5057A>G is a missense variant. BP7_Strong (RNA) would require well-established functional studies showing no damaging effect on mRNA transcript profile, but all functional evidence (ENIGMA Table 9 PS3_Strong, ST4 LOF) demonstrates a damaging effect. BP7_Supporting requires a silent variant inside a clinically important functional domain with BP4 met — this variant is missense, not silent, so BP7_Supporting does not apply.	cspec vcep_specifications_table9_v1_2_2024_11_18

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