Variant classification summary

NM_007294.4:c.2347A>G

BRCA1 · NP_009225.1:p.(Ile783Val) · NM_007294.4

GRCh37: chr17:41245201 T>C · GRCh38: chr17:43093184 T>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS1 strong BS3 strong BP1 strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ile783Val)

gnomAD AF

1.1153549679149555e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.2347A>G (p.Ile783Val) is observed in gnomAD at a filter allele frequency of 0.0632% (18/250,738 alleles in v2.1, grpmax FAF in East Asian population), exceeding the ENIGMA BS1_Strong threshold of 0.01%.

2

A calibrated functional study (Bouwman et al. 2020, PMID:32546644) demonstrated that p.Ile783Val exhibits protein function similar to benign control variants in a homologous recombination repair complementation assay. ENIGMA Specifications Table 9 assigns BS3_Strong to this variant.

3

The variant is a missense substitution at amino acid 783, located outside all ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), with no predicted splicing impact (SpliceAI max delta=0.0), satisfying ENIGMA BP1_Strong.

4

Three strong benign criteria (BS1, BS3, BP1) are met, satisfying ENIGMA Table 3 rule for Benign classification (≥2 Strong Benign criteria).

Final determination: Under ENIGMA BRCA1 v1.2 Table 3, two or more Strong Benign criteria result in a Benign classification.

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 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, single/multi-exon deletion) per ENIGMA BRCA1 specification v1.2. NM_007294.4:c.2347A>G is a missense variant (p.Ile783Val) and does not qualify for PVS1.	cspec
PS1	Not assessed	No previously classified pathogenic or likely pathogenic missense variant at the same residue (Ile783) was identified in available data. ENIGMA PS1 requires a same-residue comparator variant classified as pathogenic/likely pathogenic with no predicted splicing impact (SpliceAI ≤0.1). The pm5_candidates search found no eligible comparators under ENIGMA rules (PM5 repurposed for PTC variants only).	pm5_candidates
PS2	N/A	ENIGMA BRCA1 specification v1.2 designates PS2 (de novo) as Not Applicable for BRCA1.	cspec
PS3	Not met	ENIGMA Specifications Table 9 assigns BS3_Strong to c.2347A>G (p.Ile783Val), indicating calibrated functional studies demonstrate protein function similar to benign control variants (Bouwman 2020, PMID:32546644). No evidence of damaging effect on protein function was identified. Functional evidence supports benign, not pathogenic, impact for this variant.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control data available for this variant. ENIGMA PS4 requires case-control study with p-value ≤0.05 and OR ≥4 (lower CI excludes 2.0). The variant is observed in gnomAD at low frequency (East Asian AF=0.098% in v2.1), but no formal case-control comparison meeting ENIGMA thresholds was identified.	gnomad_v2
PS5	N/A	PS5 is not defined in the ENIGMA BRCA1 specification v1.2.	cspec
PM1	N/A	ENIGMA BRCA1 specification v1.2 designates PM1 as Not Applicable; domain-level considerations are captured through PP3/BP4/BP1 rules referencing clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). Position 783 lies outside all three domains.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires absence from controls in gnomAD v2.1 (non-cancer, exome) and gnomAD v3.1 (non-cancer). This variant is present in gnomAD v2.1 with 18/250,738 alleles (AF=0.0072%) and in gnomAD v4.1 with 18/1,613,836 alleles (AF=0.0011%). It is not absent from population databases.	gnomad_v2 gnomad_v4
PM5	N/A	Under ENIGMA BRCA1 specification, PM5 is repurposed for protein termination codon (PTC) variants in exons where a different proven pathogenic PTC variant has been observed, used to justify additional weight for PTC variants annotated as PVS1. This is a missense variant (p.Ile783Val); classic same-residue missense PM5 is not applied under ENIGMA rules.	cspec pm5_candidates
PM6	N/A	ENIGMA BRCA1 specification v1.2 designates PM6 (de novo) as Not Applicable for BRCA1.	cspec
PP1	Not assessed	No co-segregation data available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with LR thresholds (Supporting ≥2.08, Moderate ≥4.3, Strong ≥18.7, Very Strong ≥350). No segregation analysis was identified in available data.
PP2	N/A	ENIGMA BRCA1 specification v1.2 designates PP2 as Not Applicable for BRCA1.	cspec
PP3	Not met	ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel ≥0.28, or when SpliceAI ≥0.2. Position 783 is outside all three ENIGMA domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel score is -0.316 (below 0.28 threshold). SpliceAI max delta is 0.0 (below 0.2 threshold). Neither criterion is satisfied.	spliceai bayesdel
PP4	Not assessed	Variant c.2347A>G was not found in the ENIGMA clinical history likelihood ratio table (Li et al. 2020, PMID:31853058, BRCA1_clinical_history_LR.xlsx). No clinical-history LR is available for PP4 adjudication under ENIGMA rules.	vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	ENIGMA BRCA1 specification v1.2 designates PP5 as Not Applicable for BRCA1. ClinVar classification alone is not used as independent evidence under ENIGMA rules.	cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) >0.1% (0.001) in gnomAD v2.1 non-cancer exome and/or gnomAD v3.1 non-cancer, non-founder populations. gnomAD v2.1 grpmax FAF = 0.0632% (0.000632) and v4.1 grpmax FAF = 0.0223% (0.000223). Neither exceeds the 0.1% stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Met	ENIGMA BS1_Strong: filter allele frequency (FAF) >0.01% (0.0001) in gnomAD non-cancer, non-founder populations. This variant has grpmax FAF = 0.0632% (0.000632) in gnomAD v2.1 East Asian population (18/18,394 alleles, AF=0.098%) and grpmax FAF = 0.0223% (0.000223) in gnomAD v4.1. Both exceed the BS1_Strong threshold. The East Asian population is not a founder population under ENIGMA criteria.	gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA BS2 requires proband-level data evaluated per Specifications Table 8, applied in the absence of Fanconi Anemia phenotype features. No proband-specific phenotype data is available in the current case materials to adjudicate BS2.
BS3	Met	ENIGMA Specifications Table 9 assigns BS3_Strong to NM_007294.4:c.2347A>G (p.Ile783Val). A calibrated functional study (Bouwman 2020, PMID:32546644) demonstrated that this variant exhibits protein function similar to benign control variants in a homologous recombination repair complementation assay, indicating no damaging effect on protein function.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation (LR thresholds). No segregation data is available for this variant in current case materials.
BP1	Met	ENIGMA BP1_Strong applies to missense variants located outside a (potentially) clinically important functional domain AND with no predicted splicing impact (SpliceAI ≤0.1). p.Ile783Val is a missense variant at amino acid position 783, which is outside all three ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI max delta score is 0.0, confirming no predicted splicing impact.	cspec spliceai
BP2	N/A	ENIGMA BRCA1 specification v1.2 designates BP2 as Not Applicable for BRCA1.	cspec
BP4	Not met	ENIGMA BP4 applies to missense variants inside a clinically important functional domain with no predicted impact via protein change or splicing (BayesDel ≤0.15 AND SpliceAI ≤0.1). Position 783 is outside all three ENIGMA domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BP4 does not apply to variants outside these domains under ENIGMA rules; domain-external missense variants are captured by BP1 instead.	cspec
BP5	Not assessed	Variant c.2347A>G was not found in the ENIGMA clinical history likelihood ratio table (Li et al. 2020, PMID:31853058, BRCA1_clinical_history_LR.xlsx). No clinical-history LR against pathogenicity is available for BP5 adjudication under ENIGMA rules.	vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	ENIGMA BRCA1 specification v1.2 designates BP6 as Not Applicable for BRCA1.	cspec
BP7	Not met	ENIGMA BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile (mRNA assay only). BS3_Strong is applied for protein-level functional neutrality; BP7 requires separate mRNA-level evidence. No mRNA-specific splicing or transcript assay data is available for this variant. SpliceAI predicts no splicing impact (max delta=0.0), but BP7 under ENIGMA requires experimental mRNA data, not predictions alone. BP7_Supporting applies only to silent or intronic variants, not missense substitutions.	cspec
BP3	N/A	Skipped — ENIGMA specification captures in-frame indel considerations through other criteria; not applicable to this missense substitution.
PM3	N/A	Skipped — PM3 applies only to recessive disease (Fanconi Anemia phenotype with co-occurring BRCA1 variants); not applicable in the context of this heterozygous missense variant assessment without Fanconi Anemia phenotype data.
PM4	N/A	Skipped — ENIGMA specification designates PM4 as Not Applicable; this is a missense substitution, not an in-frame deletion/insertion or stop-loss variant.

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