Variant classification summary

NM_007294.3:c.1568T>G

BRCA1 · NP_009225.1:p.(Leu523Trp) · NM_007294.3

GRCh37: chr17:41245980 A>C · GRCh38: chr17:43093963 A>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

Likely Benign

PM2 supporting BP1 strong benign

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Leu523Trp)

gnomAD AF

6.196715988394791e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.3:c.1568T>G (p.Leu523Trp) is a missense variant in BRCA1 exon 10, located outside the clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857).

2

This variant is absent from gnomAD v2.1 (non-cancer exome subset) and present at extremely low frequency in gnomAD v4.1 (1/1,613,758 alleles; AF = 6.20e-7). The absence from the v2.1 outbred population controls meets ENIGMA PM2_Supporting.

3

The variant falls within the BRCA1 exon 11 coldspot region (aa 224-1366), where no pathogenic missense variants have been observed in ClinVar. Combined with its location outside clinically important functional domains and absence of predicted splicing impact (SpliceAI = 0.00), this meets ENIGMA BP1_Strong.

4

In silico predictors are discordant: BayesDel (0.322, ≥0.28 threshold) predicts a damaging protein change but PP3 is not triggered because the variant lies outside clinically important functional domains per ENIGMA rules. REVEL score is 0.613.

5

No functional data (PS3/BS3), segregation data (PP1/BS4), clinical-history likelihood ratios (PP4/BP5), or case-control studies (PS4) are available for this variant. It is absent from the ENIGMA Table 9 curated functional assay results and from the ST4 functional assay dataset.

6

The variant is reported in ClinVar as Uncertain significance by 6 clinical laboratories and Likely benign by 1 laboratory (ClinVar ID 54295). No expert panel classification is available.

7

With PM2_Supporting on the pathogenic side and BP1_Strong on the benign side, the evidence is conflicting and does not meet ENIGMA Table 3 thresholds for Likely Pathogenic, Likely Benign, or Benign classification. The variant remains classified as Uncertain Significance.

Final determination: Under the ENIGMA BRCA1/BRCA2 v1.2.0 conflicting-evidence point system, PM2_Supporting (+1) combined with BP1_Strong (-4) yields a net score of -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	NM_007294.3:c.1568T>G is a missense variant (p.Leu523Trp), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 is restricted to null variants under the ENIGMA BRCA1 specification.
PS1	Not met	No previously classified pathogenic or likely pathogenic missense variant at the same amino acid position (Leu523) with a different substitution has been identified in the ENIGMA specification tables, ClinVar, or the reviewed literature.	cspec
PS2	N/A	PS2 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0.	cspec
PS3	Not met	No variant-specific or systematic-range functional data is available for NM_007294.3:c.1568T>G. The variant is absent from ENIGMA Table 9 (pre-assigned PS3/BS3 codes) and absent from the ST4 functional assay results in SupplementaryTables. No functional study mentioning this variant was identified in the reviewed literature.
PS4	Not met	No case-control study demonstrating statistically significant enrichment of this variant in affected individuals versus controls has been identified. The ENIGMA specification requires p-value ≤0.05 and OR ≥4 with lower CI excluding 2.0.
PS5	N/A	PS5 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0. The variant is classified in ClinVar as Uncertain significance, not as Pathogenic by any reputable source.	cspec clinvar
PM1	N/A	PM1 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0. Additionally, amino acid position 523 lies outside the ENIGMA-defined clinically important functional domains (RING: aa 2-101, coiled-coil: aa 1391-1424, BRCT: aa 1650-1857). Position 523 falls within the exon 11 coldspot region (aa 224-1366) where no pathogenic missense variants have been reported.	cspec PMID:31911673
PM2	Met	The variant is absent from gnomAD v2.1 (non-cancer, exome only subset), meeting the ENIGMA PM2_Supporting criterion for absence from controls in an outbred population. In gnomAD v4.1, a single allele is observed (AF = 6.2e-7, 1/1,613,758 alleles, no homozygotes).	gnomad_v2 gnomad_v4
PM5	N/A	Under the ENIGMA BRCA1 specification, PM5 is repurposed for protein termination codon (PTC) variants only (PM5_PTC), applied when a PTC occurs in an exon where a proven pathogenic PTC has been observed. NM_007294.3:c.1568T>G is a missense variant, not a PTC. Classic same-residue missense PM5 also does not apply: no pathogenic missense variant at codon 523 has been identified.	cspec
PM6	N/A	PM6 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0.	cspec
PP1	Not met	No co-segregation data are available for this variant. No family studies with quantitative co-segregation analysis were identified in the reviewed literature.
PP2	N/A	PP2 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0.	cspec
PP3	Not met	Although BayesDel (0.322, ≥0.28 threshold) predicts a damaging protein change, the variant lies outside ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). Per ENIGMA PP3 rules, PP3 requires both BayesDel ≥0.28 AND location inside a clinically important functional domain for missense variants. SpliceAI delta score is 0.00 (<0.2), so the splicing-based PP3 rule does not apply.	cspec bayesdel spliceai
PP4	Not met	The variant is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table. No clinical-history LR is available for PP4 assignment under ENIGMA rules.	PMID:31853058
PP5	N/A	PP5 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0.	cspec
BA1	Not met	The variant does not meet ENIGMA BA1 threshold (filter allele frequency >0.1% in gnomAD v2.1 or v3.1). The variant is absent from gnomAD v2.1 and present at extremely low frequency in v4.1 (AF = 6.2e-7).	gnomad_v2 gnomad_v4
BS1	Not met	The variant does not meet ENIGMA BS1 thresholds. BS1_Strong requires FAF >0.0001 (0.01%) and BS1_Supporting requires FAF >0.00002 (0.002%) and ≤0.0001 in gnomAD v2.1 or v3.1. The variant is absent from v2.1 and has AF = 6.2e-7 in v4.1, below both thresholds.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in a healthy adult individual without features of Fanconi anemia has been identified in the available evidence. ENIGMA BS2 requires proband-level data showing absence of recessive disease phenotype.
BS3	Not met	No well-established functional study demonstrates absence of a damaging effect for this variant. The variant is absent from ENIGMA Table 9 (pre-assigned BS3 codes) and absent from the ST4 functional assay results. No functional study showing benign effect was identified in the reviewed literature.
BS4	Not met	No lack-of-segregation data are available for this variant. No cosegregation analysis was identified in the reviewed literature.
BP1	Met	This missense variant lies outside ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857) and no splicing impact is predicted (SpliceAI max delta = 0.00, ≤0.1). The variant falls within the BRCA1 exon 11 coldspot region (aa 224-1366), where no pathogenic missense variants have been reported. Per ENIGMA rules, BP1_Strong applies.	cspec spliceai PMID:31911673
BP2	N/A	BP2 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0.	cspec
BP4	Not met	The ENIGMA BP4 rule applies only to missense variants inside a clinically important functional domain with no predicted impact (BayesDel ≤0.15 AND SpliceAI ≤0.1), or to intronic variants outside donor/acceptor sites. This missense variant lies outside the defined functional domains, and BayesDel (0.322) exceeds the BP4 threshold of ≤0.15, so BP4 is not applicable under ENIGMA rules.	cspec bayesdel spliceai
BP5	Not met	The variant is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table. No clinical-history LR is available for BP5 assignment under ENIGMA rules.	PMID:31853058
BP6	N/A	BP6 is designated Not Applicable by the ENIGMA BRCA1 specification v1.2.0.	cspec
BP7	Not met	BP7_Strong (RNA) requires well-established mRNA assay data showing no damaging effect on splicing. Although SpliceAI predicts no splicing impact (delta = 0.00), SpliceAI alone is not a functional assay and no mRNA transcript analysis data are available for this variant. BP7_Supporting applies only to silent or intronic variants meeting BP4, which does not apply here.	cspec spliceai

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