Variant classification summary

NM_007294.3:c.5432A>G

BRCA1 · NP_009225.1:p.(Gln1811Arg) · NM_007294.3

GRCh37: chr17:41199695 T>C · GRCh38: chr17:43047678 T>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Gln1811Arg)

gnomAD AF

6.194888721213901e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3_Strong is met: three independent calibrated functional studies (Findlay 2018, Petitalot 2019, Fernandes 2019) demonstrate that p.Gln1811Arg exhibits protein function comparable to pathogenic control variants (ENIGMA Table 9; functional impact complete, IARC class 5).

2

PM2_Supporting is met: the variant is absent from gnomAD v2.1 (non-cancer exomes) and observed at extremely low frequency in gnomAD v4.1 (1/1,614,234 alleles; AF=6.19×10⁻⁷).

3

PP3 and BP4 are not met: BayesDel no-AF score of 0.192 falls in the intermediate range between the BP4 threshold (≤0.15) and the PP3 threshold (≥0.28) for variants inside the BRCT clinically important domain.

4

PP4 and BP5 are not met: the clinical-history likelihood ratio (LR=0.993 from Li et al. 2020, N=3 probands) falls within the neutral zone, neither supporting pathogenicity nor benignity.

5

PVS1, PM5, and BP1 are not applicable: PVS1 is restricted to null variants; PM5_PTC is N/A for exon E21(22) per ENIGMA Table 4; BP1 requires location outside a clinically important functional domain (Gln1811 is within the BRCT domain).

6

Under ENIGMA Table 3 combining rules, the evidence profile of one Strong criterion (PS3) plus one Supporting criterion (PM2) is insufficient to classify as Likely Pathogenic (requires ≥2 Strong, or 1 Strong + ≥2 Supporting, or 1 Strong + 1–2 Moderate). The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: ENIGMA Table 3: 1 Strong + 1 Supporting does not meet any Pathogenic or Likely Pathogenic combination; no benign criteria are met; classification defaults to Variant of Uncertain Significance (VUS).

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_007294.3:c.5432A>G is a missense variant (p.Gln1811Arg), not a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). PVS1 is restricted to null variants under the ENIGMA BRCA1 VCEP specification v1.2.0.	cspec
PS1	Not met	No same-amino-acid-change comparator variant at position Gln1811 has been independently classified as Pathogenic or Likely Pathogenic by the ENIGMA expert panel. Other missense changes at this residue (c.5431C>A p.Gln1811Lys; c.5432A>C p.Gln1811Pro; c.5432A>T p.Gln1811Leu) have PS3 functional evidence in ENIGMA Table 9 but lack finalized pathogenic classifications for PS1 application. Additionally, the variant has SpliceAI max delta of 0.00, confirming no splicing effect, which satisfies the PS1 mechanistic requirement had a comparator been available.	vcep_specifications_table9_v1_2_2024_11_18
PS2	N/A	PS2 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
PS3	Met	ENIGMA BRCA1 VCEP Table 9 assigns PS3_Strong for NM_007294.3:c.5432A>G (p.Gln1811Arg) based on three calibrated functional studies (Findlay 2018 PMID:30209399; Petitalot 2019 PMID:30257991; Fernandes 2019 PMID:30765603), all reporting protein function similar to pathogenic control variants. In the ENIGMA Supplementary Table 4 (ST4) functional assay dataset, this variant shows complete functional impact (LOF, IARC class 5 — Pathogenic) with three independent supporting publications.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control study with odds ratio and p-value meeting ENIGMA PS4 thresholds (p≤0.05, OR≥4, lower CI excludes 2.0) has been identified for this variant.
PS5	N/A	PS5 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
PM1	N/A	PM1 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (non-cancer, exome only subset). In gnomAD v4.1, one allele is observed in 1,614,234 alleles (AF=6.19×10⁻⁷; 0.00006%), in the European (non-Finnish) population. This extremely low population frequency meets the ENIGMA PM2_Supporting threshold (absent from v2.1 and v3.1 non-cancer subsets). The single allele in v4.1 at near-zero frequency does not negate this criterion.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA Table 4 specifies PM5_N/A for BRCA1 exon E21(22) (NM_007294.3 exon 22, legacy numbering), which is the exon containing c.5432. PM5_PTC is excluded for this exon per the ENIGMA specification. Additionally, this is a missense variant, not a PTC, and pm5_candidates.json confirms no classic same-residue missense comparator approach is applicable.	vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	PM6 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
PP1	Not assessed	No co-segregation data or quantitative Bayes score analysis has been identified for this variant.
PP2	N/A	PP2 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
PP3	Not met	The variant lies within the BRCT clinically important functional domain (aa 1650–1857; Gln1811). Under ENIGMA PP3 rules, a missense variant inside a clinically important domain requires a BayesDel no-AF score ≥0.28 for predicted protein impact, or SpliceAI ≥0.2 for predicted splicing impact. The BayesDel score is 0.192 (below the 0.28 threshold) and SpliceAI max delta is 0.00 (below the 0.2 threshold). Neither criterion for PP3 is satisfied.	bayesdel spliceai cspec
PP4	Not met	The clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) for this variant is LR=0.993 (LOG(LR)=−0.007, N=3 probands). This falls within the neutral zone (>0.48 and <2.08), below the PP4_Supporting threshold of LR≥2.08. ENIGMA specifies PP4 is used ONLY to capture combined LR toward pathogenicity from multifactorial likelihood clinical data.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
BA1	Not met	ENIGMA BA1 threshold requires a filter allele frequency (FAF) >0.001 (0.1%) in gnomAD v2.1 and/or v3.1 non-cancer, non-founder populations. The variant allele frequency in gnomAD v4.1 is 6.19×10⁻⁷ (0.00006%), far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Strong requires FAF >0.0001 (0.01%); BS1_Supporting requires FAF >0.00002 (0.002%) and ≤0.0001 (0.01%). The gnomAD v4.1 allele frequency of 6.19×10⁻⁷ (0.00006%) falls below both thresholds. The variant is too rare to meet BS1 at any strength.	gnomad_v4 cspec
BS2	Not assessed	No data on observation of this variant in healthy adult individuals without features of Fanconi anemia were available for ENIGMA BS2 point-based assessment.
BS3	Not met	ENIGMA Table 9 assigns PS3_Strong for this variant based on calibrated functional studies showing protein function similar to pathogenic controls. The functional evidence supports a damaging (pathogenic) effect. BS3 requires well-established functional studies showing no damaging effect; the available evidence uniformly points in the pathogenic direction.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No lack-of-segregation data or quantitative Bayes score analysis has been identified for this variant.
BP1	Not met	ENIGMA BP1_Strong applies to missense variants located outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). The variant p.Gln1811Arg resides at amino acid position 1811 within the BRCT repeat domain (aa 1650–1857), which is a designated clinically important functional domain in the ENIGMA specification. BP1 is therefore not applicable.	cspec
BP2	N/A	BP2 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
BP4	Not met	The variant lies within the BRCT clinically important functional domain. ENIGMA BP4 requires BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1 for missense variants inside a clinically important domain. SpliceAI max delta is 0.00 (≤0.1, met), but the BayesDel no-AF score is 0.192, which exceeds the 0.15 threshold. BP4 is therefore not satisfied.	bayesdel spliceai cspec
BP5	Not met	The clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) for this variant is LR=0.993. The ENIGMA BP5_Supporting threshold is LR ≤0.48. The observed LR of 0.993 falls in the neutral zone and does not meet the BP5 threshold at any strength.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is marked Not Applicable in the ENIGMA BRCA1 CSPEC framework.	cspec
BP7	Not met	ENIGMA BP7_Strong (RNA) applies to missense variants located outside a clinically important functional domain with mRNA evidence of no splicing impact. The variant is inside the BRCT domain (aa 1650–1857), excluding BP7_Strong. BP7_Supporting is reserved for silent variants inside clinically important domains when BP4 is met; this variant is a missense substitution. No BP7 strength is applicable.	cspec

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