Variant classification summary

NM_007294.3:c.1233T>G

BRCA1 · NP_009225.1:p.(Asp411Glu) · NM_007294.3

GRCh37: chr17:41246315 A>C · GRCh38: chr17:43094298 A>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Asp411Glu)

gnomAD AF

4.25197185194634e-05 (v2.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.3:c.1233T>G (p.Asp411Glu) is a missense variant in BRCA1 exon 10, classified as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 41804).

2

This variant is present in gnomAD v2.1 at 12/282,222 alleles (AF=4.25e-05) with a grpmax filter allele frequency of 0.024% (0.00024454) in the African/African American subpopulation (11/24,934 alleles), exceeding the ENIGMA BS1_Strong threshold of >0.01%.

3

ENIGMA Table 9 (v1.2.0) assigns BS3_Strong to this variant based on calibrated functional assay evidence from Bouwman et al. 2020 (PMID:32546644), demonstrating protein function in homologous recombination repair complementation similar to benign control variants.

4

Codon 411 is located outside all three (potentially) clinically important functional domains defined by ENIGMA for BRCA1: RING finger (aa 2-101), coiled-coil (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI predicts no splicing impact (max delta score 0.07). These findings satisfy ENIGMA BP1_Strong criteria.

5

Parsons et al. 2019 multifactorial likelihood analysis (PMID:31131967) reports a combined LR of 1.29, a segregation LR of 1.93, and a family history LR of 6.48 for this variant. The combined LR is in the neutral range and does not independently support either pathogenic (PP4) or benign (BP5) classification.

6

No evidence was found to support any pathogenic criterion. PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM2, PM5, PM6, PP1, PP2, PP3, PP4, and PP5 are all either not met or not applicable.

7

Under the ENIGMA Table 3 combination rules, two or more Strong Benign criteria support a Benign classification. The three Strong Benign criteria met (BS1_Strong, BS3_Strong, BP1_Strong) satisfy the Benign classification threshold.

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	PVS1 is not applicable to missense variants. NM_007294.3:c.1233T>G (p.Asp411Glu) is a missense substitution, not a null variant (nonsense, frameshift, or canonical splice site).
PS1	Not met	No previously classified pathogenic or likely pathogenic missense variant at codon 411 with the same amino acid change (p.Asp411Glu) was identified. No known pathogenic variant at this residue with the same predicted protein effect.
PS2	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules this criterion not applicable.	cspec
PS3	Not met	ENIGMA Table 9 (v1.2.0) assigns BS3_Strong for this variant, not PS3. Functional evidence from calibrated assays (Bouwman 2020, PMID:32546644) demonstrates protein function similar to benign control variants, supporting a benign interpretation rather than a damaging effect.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not met	No case-control study has demonstrated significantly increased prevalence of this variant in affected individuals (p≤0.05, OR≥4). The variant is observed in gnomAD population controls (12/282,222 alleles), inconsistent with pathogenic enrichment.	gnomad_v2
PS5	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules PP5 not applicable; PS5 is similarly excluded from the ENIGMA framework as a source-based criterion redundant with expert panel review.	cspec
PM1	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules PM1 not applicable. Additionally, position 411 is outside the three (potentially) clinically important functional domains defined by ENIGMA: RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857).	cspec
PM2	Not met	ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). This variant is present in gnomAD v2.1 at 12/282,222 alleles (AF=4.25e-05) with grpmax FAF=0.00024454, and is absent from gnomAD v4.1. The presence in gnomAD v2.1 precludes application of PM2_Supporting.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA repurposes PM5 exclusively for PTC (protein termination codon) variants, not for classic same-residue missense comparisons. NM_007294.3:c.1233T>G is a missense variant (p.Asp411Glu) and is not a PTC.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules this criterion not applicable.	cspec
PP1	Not assessed	No co-segregation data demonstrating segregation of this variant with disease in multiple affected family members was identified. Parsons et al. 2019 (PMID:31131967) reports a segregation LR of 1.93 for this variant, which is in the neutral range (LR <2.08) and does not support co-segregation with disease.	vcep_humu_40_1557_s001
PP2	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules this criterion not applicable.	cspec
PP3	Not met	ENIGMA PP3 requires either (a) missense variant inside a clinically important functional domain with BayesDel no-AF score ≥0.28, or (b) SpliceAI delta score ≥0.2. Position 411 is outside all three clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI max delta score is 0.07 (<0.2). Neither condition is met.	cspec spliceai bayesdel
PP4	Not met	ENIGMA PP4 uses multifactorial combined likelihood ratio toward pathogenicity. Parsons et al. 2019 (PMID:31131967) reports a combined LR of 1.29 for this variant, which falls below the PP4_Supporting threshold of ≥2.08. The variant is not listed in the Li et al. 2020 clinical-history LR table (PMID:31853058). The combined multifactorial evidence is neutral.	vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules this criterion not applicable.	cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer). gnomAD v2.1 grpmax FAF is 0.00024454 (0.024%), below the 0.1% threshold. The variant is absent from gnomAD v4.1.	gnomad_v2 gnomad_v4
BS1	Met	ENIGMA BS1_Strong applies when FAF exceeds 0.01% (FAF > 0.0001). gnomAD v2.1 grpmax FAF is 0.00024454 (0.024%); the variant is observed in 12/282,222 total alleles (AF=4.25e-05) with highest subpopulation frequency in the African/African American population (11/24,934 alleles, AF=0.044%). This exceeds the ENIGMA BS1_Strong threshold of >0.01%.	gnomad_v2 cspec
BS2	Not assessed	ENIGMA BS2 requires proband-level data demonstrating observation in a healthy adult in the absence of Fanconi Anemia phenotype. No such proband data was available for this variant.
BS3	Met	ENIGMA Table 9 (v1.2.0) explicitly assigns BS3_Strong for NM_007294.3:c.1233T>G (p.Asp411Glu). One calibrated functional study (Bouwman et al. 2020, PMID:32546644) demonstrates that this variant exhibits protein function similar to benign control variants in homologous recombination repair complementation assays, meeting the criteria for well-established functional evidence of no damaging effect.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not met	ENIGMA BS4 requires a segregation LR ≤0.48 (Supporting) or lower for stronger evidence levels. Parsons et al. 2019 (PMID:31131967) reports a segregation LR of 1.93 for this variant, which does not meet even the BS4_Supporting threshold of ≤0.48. The available segregation data does not support lack of segregation with disease.	vcep_humu_40_1557_s001
BP1	Met	ENIGMA BP1_Strong applies to missense variants located outside all (potentially) clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). Codon 411 is outside the three defined domains: RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857). SpliceAI max delta score is 0.07 (≤0.1). Both conditions for BP1_Strong are satisfied.	cspec spliceai
BP2	N/A	ENIGMA BRCA1/BRCA2 VCEP v1.2.0 rules this criterion not applicable.	cspec
BP4	N/A	ENIGMA BP4_Supporting applies exclusively to missense variants located inside a (potentially) clinically important functional domain with BayesDel no-AF score ≤0.15 and SpliceAI ≤0.1. Codon 411 is outside all three defined domains. While BayesDel (-0.196) and SpliceAI (0.07) would satisfy the computational thresholds, the domain location requirement is not met, so BP4 does not apply under ENIGMA rules.	cspec bayesdel spliceai
BP5	Not met	ENIGMA BP5 uses multifactorial combined likelihood ratio against pathogenicity. Parsons et al. 2019 (PMID:31131967) reports a combined LR of 1.29 for this variant, which is above the BP5_Supporting threshold of ≤0.48. The variant is not listed in the Li et al. 2020 clinical-history LR table (PMID:31853058). The combined multifactorial evidence does not support a benign interpretation via BP5.	vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	Not met	ENIGMA BP7_Strong(RNA) requires well-established mRNA transcript assay evidence showing no damaging effect on splicing for missense variants outside clinically important functional domains. No variant-specific mRNA splicing assay data was identified for NM_007294.3:c.1233T>G. SpliceAI predicts no splicing impact (max delta=0.07) but computational prediction alone does not satisfy the ENIGMA requirement for BP7(RNA). ENIGMA BP7_Supporting applies only to silent variants inside domains and is not applicable here.	cspec spliceai

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