Variant classification summary

NM_007294.4:c.4720G>T

BRCA1 · NP_009225.1:p.(Asp1574Tyr) · NM_007294.4

GRCh37: chr17:41223211 C>A · GRCh38: chr17:43071194 C>A

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

PM2 supporting BP1 strong benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Asp1574Tyr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.4720G>T (p.Asp1574Tyr) is a missense variant in BRCA1 exon 15, located outside all three clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). It is absent from gnomAD v2.1 and v4.1 population databases.

2

The variant meets PM2_Supporting: absent from gnomAD controls in outbred populations, per ENIGMA specifications.

3

The variant meets BP1_Strong: missense substitution outside clinically important functional domains with no predicted splicing impact (SpliceAI max delta 0.02). Per ENIGMA Figure 1A, missense variants outside domains with SpliceAI ≤0.1 receive BP1_Strong.

4

PVS1, PS1, PM5, and several other criteria are not applicable as this is a missense variant without a same-residue pathogenic comparator and without null-variant features.

5

PS3 could not be assessed through the ENIGMA framework as the variant is not listed in Table 9 (calibrated functional assays). External functional evidence (Carvalho 2007 PMID:17308087, Starita 2018 PMID:29892012) suggests a damaging effect in yeast transcription and multiplex HDR assays, but these have not been calibrated through ENIGMA standards. Human review is recommended.

6

PP4 and BP5 could not be assessed: the variant is absent from the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table.

7

PS4, PP1, BS2, BS4, and BP7 have no supporting evidence available for this variant. BS3 is not met as functional evidence points toward damaging effect rather than benign.

Final determination: ENIGMA BRCA1/2 v1.2.0 Table 3 conflicting-evidence point system: when both pathogenic and benign criteria are met, sum the point values (Supporting pathogenic +1, Strong benign -4) and map to ranges (Likely Benign = -6 to -2), yielding Likely Benign at -3 points.

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_007294.4:c.4720G>T is a missense substitution (p.Asp1574Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). SpliceAI max delta score is 0.02, excluding splicing-related PVS1 (RNA). ENIGMA BRCA1 Table 4 PVS1 rules apply only to null/splice variants in exon 15; missense variants are not eligible.	pvs1_variant_assessment spliceai cspec
PS1	Not met	No known pathogenic or likely pathogenic missense variant has been identified at the same amino acid residue (Asp1574) to serve as a comparator. The pm5_candidates search identified zero same-residue candidates with expert panel pathogenic classification.	pm5_candidates cspec
PS2	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares PS2 not applicable for BRCA1/BRCA2 variant interpretation.	cspec
PS3	Not assessed	ENIGMA PS3 rule directs to Specifications Table 9 for calibrated functional assay code assignment. c.4720G>T is not listed in Table 9 and no ENIGMA-pre-assigned PS3 code exists. External functional evidence was identified (Carvalho et al. 2007 PMID:17308087 reported impaired transcription in yeast assay; Starita et al. 2018 PMID:29892012 reported reduced HDR activity in multiplex assay), but these assays have not been calibrated through the ENIGMA framework. Human review is required to determine if these functional studies meet ENIGMA PS3 calibration standards.	cspec
PS4	Not met	ENIGMA PS4 requires case-control data with p≤0.05 and OR≥4 (lower CI excludes 2.0). No case-control study or cohort analysis demonstrating enrichment of this variant in affected individuals versus controls is available. The variant is absent from gnomAD population databases, consistent with rarity, but this alone does not satisfy PS4.	clinvar gnomad_v2 gnomad_v4 cspec
PS5	N/A	PS5 is not included in the ENIGMA BRCA1/2 specification v1.2.0 criteria set. This criterion is not used by the governing VCEP framework.	cspec
PM1	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares PM1 not applicable. Additionally, the variant resides at amino acid 1574, which lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857).	cspec
PM2	Met	The variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in outbred populations, meeting ENIGMA PM2_Supporting criteria for absent from controls.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	ENIGMA repurposes PM5 as PM5_PTC, applicable only to protein-truncating codon (PTC) variants that already meet PVS1, to provide additional weight based on exon-level PTC prevalence. c.4720G>T is a missense variant (p.Asp1574Tyr) and does not qualify as a PTC. Classic same-residue missense PM5 is not used in the ENIGMA framework.	pm5_candidates cspec
PM6	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares PM6 not applicable for BRCA1/BRCA2 variant interpretation.	cspec
PP1	Not met	ENIGMA PP1 requires quantitative cosegregation analysis demonstrating co-segregation with disease in multiple affected family members (LR≥2.08 for supporting). No published cosegregation data involving this variant was identified.	cspec
PP2	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares PP2 not applicable for BRCA1/BRCA2 variant interpretation.	cspec
PP3	Not met	ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel ≥0.28, or variants with SpliceAI ≥0.2 irrespective of domain location. p.Asp1574Tyr lies outside all BRCA1 functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), BayesDel no-AF score is 0.109 (<0.28), and SpliceAI max delta is 0.02 (<0.2). Neither condition for PP3 is met.	revel bayesdel spliceai cspec
PP4	Not assessed	ENIGMA PP4 uses calibrated clinical-history likelihood ratios from Li et al. 2020 (PMID:31853058). The variant NM_007294.4:c.4720G>T was not found in the BRCA1 clinical_history_LR table. No alternative multifactorial clinical likelihood data are available. PP4 cannot be assessed without variant-specific LR data.	vcep_pmid_31853058_brca1_clinical_history_lr cspec
PP5	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares PP5 not applicable for BRCA1/BRCA2 variant interpretation.	cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome) and/or gnomAD v3.1 (non-cancer). The variant is absent from gnomAD v2.1 and v4.1. BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	ENIGMA BS1 requires FAF > 0.01% (strong) or FAF > 0.002% and ≤ 0.01% (supporting) in gnomAD non-founder populations. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 requires observation in healthy adults without features of Fanconi anemia. No data on observations of this variant in healthy adult controls beyond gnomAD absence were identified. BS2 cannot be assessed without dedicated control cohort data.	cspec
BS3	Not met	ENIGMA BS3 requires well-established functional studies showing no damaging effect on protein function. The variant is not listed in ENIGMA Table 9 with a BS3 assignment. External functional evidence (Carvalho et al. 2007 PMID:17308087; Starita et al. 2018 PMID:29892012) indicates a damaging rather than benign functional effect. BS3 is not met; the available evidence points in the opposite direction (damaging).	cspec
BS4	Not assessed	ENIGMA BS4 requires quantitative lack-of-segregation data (LR ≤0.48 for supporting, ≤0.23 for moderate, ≤0.05 for strong). No segregation data of any kind were identified for this variant. BS4 cannot be assessed.	cspec
BP1	Met	ENIGMA BP1_Strong applies to missense variants located outside all clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). p.Asp1574Tyr lies at amino acid 1574, outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. SpliceAI max delta score is 0.02 (≤0.1), confirming no predicted splice impact.	spliceai cspec bayesdel
BP2	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares BP2 not applicable for BRCA1/BRCA2 variant interpretation.	cspec
BP4	Not met	ENIGMA BP4 (supporting benign from computational evidence) applies to missense variants inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. Since p.Asp1574Tyr lies outside all BRCA1 functional domains, the primary BP4 rule for missense variants is not triggered. Although BayesDel (0.109) and SpliceAI (0.02) both fall below the specified thresholds, the domain location requirement is not satisfied.	bayesdel spliceai cspec
BP5	Not assessed	ENIGMA BP5 uses calibrated clinical-history likelihood ratios from Li et al. 2020 (PMID:31853058). The variant NM_007294.4:c.4720G>T was not found in the BRCA1 clinical_history_LR table. No alternative multifactorial clinical likelihood data are available. BP5 cannot be assessed without variant-specific LR data.	vcep_pmid_31853058_brca1_clinical_history_lr cspec
BP6	N/A	ENIGMA BRCA1/2 specification v1.2.0 declares BP6 not applicable for BRCA1/BRCA2 variant interpretation.	cspec
BP7	Not met	ENIGMA BP7_Strong (RNA) requires well-established mRNA assay data demonstrating no splicing aberration. ENIGMA BP7_Supporting applies to silent/intronic variants under specific conditions, not to missense variants outside functional domains. No mRNA transcript analysis data were identified for this variant. SpliceAI prediction alone is insufficient to meet BP7.	spliceai cspec

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