Variant classification summary

NM_007294.4:c.670G>A

BRCA1 · NP_009225.1:p.(Ala224Thr) · NM_007294.4

GRCh37: chr17:41247863 C>T · GRCh38: chr17:43095846 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

BP1 strong PM2 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ala224Thr)

gnomAD AF

6.200289181487424e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.670G>A (p.Ala224Thr) is a missense variant in BRCA1 exon 9(10).

2

This variant is absent from gnomAD v2.1 and present as a singleton in gnomAD v4.1 (1/1,612,828 alleles, AF=6.2e-7), meeting PM2_Supporting under the ENIGMA BRCA1 VCEP specification v1.2.0.

3

BP1_Strong is applied: the variant is a missense substitution located at amino acid position 224, which lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no splicing impact (max delta = 0.00).

4

BayesDel no-AF score is 0.183, falling in the intermediate zone between BP4 (≤0.15) and PP3 (≥0.28); REVEL score is 0.541. Neither PP3 nor BP4 can be applied.

5

The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 1.76 based on 1 proband, falling in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 is applicable.

6

No functional assay data (PS3/BS3), case-control data (PS4), co-segregation data (PP1/BS4), or same-residue pathogenic comparator (PS1) was identified for this variant.

7

Under the ENIGMA Table 3 combining rules, the evidence consists of BP1_Strong (1 strong benign) and PM2_Supporting (1 supporting pathogenic). This combination does not satisfy any Pathogenic, Likely Pathogenic, Likely Benign, or Benign classification rule. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Conflicting pathogenic and benign evidence resolved via ENIGMA Table 3 point system: BP1_Strong (-4 benign points) + PM2_Supporting (+1 pathogenic point) = -3, which falls in the Likely Benign range (-6 to -2).

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 under the ENIGMA BRCA1 VCEP. NM_007294.4:c.670G>A is a missense substitution (p.Ala224Thr), not a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). SpliceAI predicts no splicing impact (max delta = 0.0).	cspec spliceai pvs1_variant_assessment
PS1	Not met	No previously classified pathogenic missense variant at the same amino acid position (p.Ala224) was identified. The only same-codon comparator c.670G>C (p.Ala224Pro) is listed in ENIGMA Table 9 with no assigned PS3/BS3 code (PS3/BS3 not met) and has predicted splicing impact, whereas c.670G>A has no splicing impact (SpliceAI=0.0). No pathogenic comparator satisfies the PS1 rule requirements.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS2	N/A	PS2 (de novo) is not part of the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0 criteria set. PM6 (also de novo) is explicitly marked Not Applicable by the CSPEC framework.	cspec
PS3	Not met	No well-established functional assay data demonstrating a damaging effect on BRCA1 protein function was identified for c.670G>A. ENIGMA Specifications Table 9 (calibrated functional studies) does not list this variant. ST4 functional assay dataset does not contain c.670G>A. No variant-specific functional evidence was found in the literature.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not met	No case-control data demonstrating significantly increased prevalence of c.670G>A in affected individuals versus controls was identified. The variant is absent from ClinVar and no published studies report variant counts in breast/ovarian cancer cohorts.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 is not part of the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0 criteria set.	cspec
PM1	N/A	PM1 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0.	cspec
PM2	Met	PM2_Supporting is met under ENIGMA rules. The variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and present as a singleton in gnomAD v4.1 (1/1,612,828 alleles, AF=6.2e-7), consistent with absence from controls in an outbred population. The region around the variant has adequate read depth.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	PM5 in the ENIGMA BRCA1 VCEP is repurposed exclusively for protein termination codon (PTC) variants in exons where a proven pathogenic PTC has been observed (PM5_PTC). c.670G>A is a missense variant, not a PTC.	cspec pm5_candidates
PM6	N/A	PM6 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0.	cspec
PP1	Not met	No co-segregation data was identified for c.670G>A. No family studies or pedigrees demonstrating segregation of this variant with breast/ovarian cancer in affected family members were found in public databases (ClinVar, LOVD, BRCA Exchange) or the literature.	clinvar
PP2	N/A	PP2 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0.	cspec
PP3	Not met	PP3 is not met under ENIGMA rules. The variant (p.Ala224Thr, position 224) lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel no-AF score (0.183) is below the ≥0.28 threshold. SpliceAI max delta (0.00) is below the ≥0.2 threshold. No predicted impact via protein change or splicing.	bayesdel spliceai revel cspec
PP4	Not met	PP4 is not met. The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.76 (based on 1 proband), which falls in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 can be applied.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	PP5 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0.	cspec
BA1	Not met	BA1 is not met. The variant frequency in gnomAD is well below the ENIGMA BA1 threshold (FAF > 0.1%). gnomAD v2.1: absent. gnomAD v4.1: AF=6.2e-7 (0.000062%).	gnomad_v2 gnomad_v4 cspec
BS1	Not met	BS1 is not met. The variant frequency is below both the BS1_Strong threshold (FAF > 0.01%) and the BS1_Supporting threshold (FAF > 0.002%). gnomAD v2.1: absent. gnomAD v4.1: AF=6.2e-7 (0.000062%), below the 0.002% (2e-5) BS1_Supporting threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	BS2 requires observation of the variant in trans with a pathogenic variant in healthy individuals (absence of Fanconi anemia phenotype). No such data is available for c.670G>A.
BS3	Not met	No well-established functional assay data demonstrating no damaging effect on BRCA1 protein function was identified for c.670G>A. ENIGMA Specifications Table 9 does not list this variant for BS3. ST4 functional assay dataset contains no entry for c.670G>A.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not met	No lack of segregation data was identified for c.670G>A. No study reports affected family members who do not carry this variant.
BP1	Met	BP1_Strong is met under ENIGMA rules. c.670G>A is a missense variant (p.Ala224Thr) located at amino acid position 224, which is outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI predicts no splicing impact (max delta = 0.00, ≤0.1). All conditions for BP1_Strong are satisfied.	cspec spliceai
BP2	N/A	BP2 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0.	cspec
BP4	Not met	BP4 is not met. The primary BP4 rule requires the variant to be inside a clinically important functional domain with BayesDel ≤0.15 and SpliceAI ≤0.1. Position 224 is outside all three functional domains. Additionally, BayesDel no-AF score (0.183) exceeds the ≤0.15 threshold. The intronic BP4 rule does not apply as this is an exonic variant.	bayesdel spliceai cspec
BP5	Not met	BP5 is not met. The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.76 (1 proband), which falls in the neutral zone (>0.48 and <2.08). BP5 Supporting requires LR ≤0.48.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	BP6 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0.	cspec
BP7	Not met	BP7 is not met. BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile — no such data exists for c.670G>A. BP7_Supporting applies only to silent variants inside functional domains (if BP4 met) or intronic variants at positions ≥+7/-21 (if BP4 met). This variant is a missense outside functional domains and is exonic.	cspec spliceai

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