Variant classification summary

NM_007294.4:c.1367T>C

BRCA1 · NP_009225.1:p.(Ile456Thr) · NM_007294.4

GRCh37: chr17:41246181 A>G · GRCh38: chr17:43094164 A>G

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

BP1 strong BP5 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ile456Thr)

gnomAD AF

3.097728373828904e-06 (v4.1)

ClinVar

Conflicting classifications of pathogenicity

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.1367T>C (p.Ile456Thr) is a missense substitution in BRCA1 exon 10(11) at amino acid position 456, which lies outside the recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857).

2

BP1_Strong is met: the variant is a missense substitution outside all clinically important functional domains with no splicing predicted (SpliceAI max delta = 0.00), satisfying the ENIGMA v1.2.0 BP1_Strong rule.

3

BP5_Supporting is met: clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 0.34 (LOG(LR) = −1.078) based on 4 probands, meeting the BP5_Supporting threshold of LR ≤ 0.48.

4

The Parsons et al. 2019 (PMID:31131967) combined multifactorial analysis yielded a combined LR of 0.797 (moderate in favour of benign), directionally consistent with the Li 2020 clinical-history finding, though not independently meeting ENIGMA BP5 thresholds.

5

No pathogenic evidence criteria are met. The variant is present in gnomAD at extremely low frequency (v2.1: 2/251,050 alleles, AF=0.0008%; v4.1: 5/1,614,086 alleles) and is reported in ClinVar with conflicting classifications (Variation ID: 54222). No functional studies, case-control data, co-segregation data, or variant-specific literature were identified.

6

Under ENIGMA BRCA1 v1.2.0 Table 3 combination rules, 1 Strong Benign criterion (BP1_Strong) plus 1 Supporting Benign criterion (BP5_Supporting) meets the threshold for Likely Benign.

Final determination: ENIGMA BRCA1/2 v1.2.0 Table 3 Likely Benign rule: 1 Strong (Benign) criterion plus 1 Supporting (Benign) criterion yields a Likely 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	NM_007294.4:c.1367T>C is a missense substitution (p.Ile456Thr), not a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). ENIGMA BRCA1 PVS1 is restricted to null variants.	cspec
PS1	Not met	No previously classified pathogenic or likely pathogenic variant resulting in the same amino acid change (Ile456Thr) or a different missense at codon 456 was identified in ClinVar or ENIGMA reference datasets. ENIGMA Table 9 and ST4 contain no functional or classificatory data for this codon.	cspec clinvar vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	ENIGMA BRCA1 v1.2.0 lists PS2 (de novo) as Not Applicable.	cspec
PS3	Not met	NM_007294.4:c.1367T>C (p.Ile456Thr) was not found in ENIGMA Specifications Table 9 (curated functional assay results) or Supplementary Table 4 (full functional assay dataset). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No variant-specific functional studies were identified in the literature. BRCA1 amino acid 456 lies outside the recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857) and is not within a domain characterized by systematic saturation mutagenesis or tiling screens.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
PS4	Not met	No case-control study with p-value ≤0.05 and OR ≥4 (lower CI excludes 2.0) was identified for this variant. The literature papers associated with this case are clinical practice guidelines (ACS, NSGC, USPSTF, ASCO), which do not provide variant-specific case-control data. The variant is present in gnomAD at extremely low frequency (AF=0.0008% in v2.1) but no case-control enrichment analysis is available.	cspec gnomad_v2
PS5	N/A	PS5 (same amino acid change as established pathogenic variant regardless of nucleotide change) is not defined as a standalone criterion in the ENIGMA BRCA1 v1.2.0 specification; this scenario is captured by PS1 within the ENIGMA framework.	cspec
PM1	N/A	ENIGMA BRCA1 v1.2.0 lists PM1 as Not Applicable.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome-only) and gnomAD v3.1 (non-cancer) in outbred populations. This variant is present in gnomAD v2.1 with 2 alleles (AF=7.97×10⁻⁶, 2/251,050 exomes) and in gnomAD v4.1 with 5 alleles (AF=3.10×10⁻⁶). Presence in population databases, even at extremely low frequency, precludes application of PM2_Supporting under ENIGMA rules.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	Under ENIGMA BRCA1 v1.2.0, PM5 is repurposed exclusively for protein termination codon (PTC) variants (PM5_PTC), applied as additional weight for PTC variants already annotated with PVS1. NM_007294.4:c.1367T>C is a missense substitution, not a PTC variant. Classic same-residue-missense PM5 is not part of the ENIGMA framework for BRCA1.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	ENIGMA BRCA1 v1.2.0 lists PM6 (de novo, maternity/paternity not confirmed) as Not Applicable.	cspec
PP1	Not met	No co-segregation data are available for NM_007294.4:c.1367T>C. ENIGMA PP1 requires quantitative co-segregation analysis with likelihood ratio exceeding defined thresholds (LR≥2.08 for Supporting, ≥4.3 for Moderate, ≥18.7 for Strong). No such analysis was identified.	cspec
PP2	N/A	ENIGMA BRCA1 v1.2.0 lists PP2 (missense in gene with low rate of benign missense variation) as Not Applicable.	cspec
PP3	Not met	ENIGMA PP3 for missense variants requires the variant to be inside a clinically important functional domain (RING aa 2–101, coiled-coil aa 1391–1424, or BRCT aa 1650–1857) AND BayesDel no-AF score ≥0.28. p.Ile456Thr is at position 456, outside all three recognized domains. Additionally, SpliceAI max delta=0.00 (<0.2 threshold for splicing-based PP3) and BayesDel=0.122 (<0.28). None of the ENIGMA PP3 triggers are met.	cspec spliceai bayesdel revel
PP4	Not met	ENIGMA PP4 uses the clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058). For NM_007294.4:c.1367T>C, LOG(LR) = −1.078, LR = 0.34 (N=4 probands). This falls in the benign direction, well below the PP4_Supporting threshold of LR≥2.08. The Parsons et al. 2019 (PMID:31131967) combined multifactorial LR = 0.797 also falls in the neutral-to-benign range, consistent with no pathogenic signal.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001 cspec
PP5	N/A	ENIGMA BRCA1 v1.2.0 lists PP5 (reputable source = pathogenic) as Not Applicable. ClinVar lists this variant with conflicting classifications (Variation ID: 54222) and review status 'criteria provided, conflicting classifications'; no expert panel submission exists.	cspec clinvar
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% (>0.001) in gnomAD v2.1 (non-cancer, exome-only) and/or v3.1 (non-cancer) non-founder populations. gnomAD v2.1 AF = 7.97×10⁻⁶ (0.0008%); gnomAD v4.1 grpmax FAF = 6.8×10⁻⁷ (0.000068%). Both are orders of magnitude below the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Supporting requires FAF > 0.002% (>0.00002) and ≤0.01% in gnomAD non-cancer, non-founder populations. BS1_Strong requires FAF > 0.01% (>0.0001). gnomAD v2.1 AF = 0.0008% (below 0.002%); gnomAD v4.1 grpmax FAF = 0.000068% (below 0.002%). Both values fall below even the BS1_Supporting threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	ENIGMA BS2 requires evaluation using Specifications Table 8 points system based on observations in individuals without a Fanconi anemia phenotype. No proband-level observational data (age, phenotype, co-occurrence) are available for NM_007294.4:c.1367T>C to perform this points-based assessment.	cspec
BS3	Not met	NM_007294.4:c.1367T>C (p.Ile456Thr) was not found in ENIGMA Specifications Table 9 (curated functional assay results with pre-assigned BS3 strengths) or Supplementary Table 4 (full functional assay dataset). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No studies demonstrating no damaging effect on protein function were identified for this variant.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
BS4	Not met	No lack-of-segregation data are available for NM_007294.4:c.1367T>C. ENIGMA BS4 requires quantitative co-segregation analysis with likelihood ratio ≤0.48 (Supporting), ≤0.23 (Moderate), or ≤0.05 (Strong). No such analysis was identified.	cspec
BP1	Met	ENIGMA BP1_Strong applies to missense variants located outside all (potentially) clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857) with no splicing predicted (SpliceAI ≤0.1). p.Ile456Thr is at position 456, outside all three domains. SpliceAI max delta = 0.00. Both conditions satisfied for BP1_Strong.	cspec spliceai
BP2	N/A	ENIGMA BRCA1 v1.2.0 lists BP2 (observed in trans with pathogenic variant in recessive disorder) as Not Applicable.	cspec
BP4	Not met	ENIGMA BP4_Supporting for missense variants requires the variant to be inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. Although BayesDel (0.122) and SpliceAI (0.00) satisfy the in silico thresholds, p.Ile456Thr is at position 456, which lies outside all three recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857). The domain location requirement is not met.	cspec bayesdel spliceai
BP5	Met	ENIGMA BP5 captures combined likelihood ratio against pathogenicity from multifactorial likelihood clinical data. For NM_007294.4:c.1367T>C, the clinical-history LR from Li et al. 2020 (PMID:31853058) is 0.34 (LOG(LR) = −1.078, N=4 probands). This meets the BP5_Supporting threshold (LR ≤ 0.48). The Parsons et al. 2019 (PMID:31131967) combined multifactorial LR of 0.797 (co-occurrence LR=1.139, pathology LR=0.700) is directionally consistent with a benign interpretation but falls in the neutral zone for BP5. Only the Li 2020 clinical-history LR is used for code assignment per ENIGMA specifications.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001 cspec
BP6	N/A	ENIGMA BRCA1 v1.2.0 lists BP6 (reputable source = benign) as Not Applicable. Even if assessed under generic ACMG, ClinVar reports conflicting classifications with no expert panel consensus for this variant (Variation ID: 54222).	cspec clinvar
BP7	Not met	ENIGMA BP7_Strong (RNA) requires well-established in vitro or in vivo functional studies showing no damaging effect on mRNA transcript profile. No mRNA splicing assay data were identified for NM_007294.4:c.1367T>C. The variant is not listed in ENIGMA Supplementary Table 3 (splicing references). ENIGMA BP7_Supporting applies only to silent variants inside clinically important domains (with BP4 met) or deep intronic variants, neither of which applies to this missense substitution. SpliceAI max delta = 0.00, consistent with no predicted splicing impact, but this alone does not trigger BP7 under ENIGMA rules.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18

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