Variant classification summary

NM_007294.4:c.2531G>C

BRCA1 · NP_009225.1:p.(Ser844Thr) · NM_007294.4

GRCh37: chr17:41245017 C>G · GRCh38: chr17:43093000 C>G

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

PM2 supporting BP1 strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ser844Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.2531G>C (p.Ser844Thr) is a missense variant in BRCA1 exon 10, absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

2

The variant is located at residue 844, outside ENIGMA-defined 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), meeting BP1_Strong.

3

No functional assay data are available for this variant in ENIGMA-calibrated studies (PS3/BS3 not met). The variant was searched in the ENIGMA Table 9 curated functional assay results, ST4 full functional dataset, ST5 mammalian functional studies, and Parsons et al. 2019 datasets and was not found in any.

4

No clinical-history likelihood ratio is available from Li et al. 2020 (PMID:31853058) for this variant; c.2531G>C was not present in the BRCA1 clinical_history_LR table (PP4/BP5 not met).

5

Under the ENIGMA point system for conflicting evidence (Table 3), PM2_Supporting (+1) and BP1_Strong (-4) sum to -3, which falls in the Likely Benign range (-6 to -2). The variant is classified as Likely Benign.

Final determination: ENIGMA BRCA1/BRCA2 v1.2 Table 3 conflicting evidence point system: PM2_Supporting (+1 pathogenic) + BP1_Strong (-4 benign) = -3 total points, which maps to 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_007294.4:c.2531G>C is a missense substitution (p.Ser844Thr), not a null variant (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion). PVS1 applies only to null variants under the ENIGMA BRCA1/2 specification v1.2.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not met	No previously classified pathogenic or likely pathogenic missense variant at BRCA1 codon 844 (p.Ser844) was identified in the ENIGMA reference variant set (ST7), curated functional assay table (Table 9), or the Parsons et al. 2019 multifactorial dataset (HUMU-40-1557-s001). Without a pathogenic comparator at the same residue, PS1 cannot be applied.	vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PS2	N/A	ENIGMA BRCA1/2 specification v1.2 marks PS2 as Not Applicable.	cspec
PS3	Not met	c.2531G>C (p.Ser844Thr) is not listed in the ENIGMA Table 9 curated functional assay results. It was also absent from the full ST4 functional assay dataset (4,304 rows), ST5 BRCA1 mammalian functional studies, and the Parsons et al. 2019 functional assay cross-reference (SuppT4). No variant-specific functional evidence was identified in any ENIGMA-calibrated study.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PS4	Not met	No case-control data demonstrating significantly increased prevalence in affected individuals versus controls (p≤0.05, OR≥4) are available for this variant. The variant is absent from gnomAD but there are no proband counts or case-control comparisons to satisfy the ENIGMA PS4 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PS5	Not met	PS5 requires both PS1 and PM5 to be met. Neither PS1 (no pathogenic comparator at codon 844) nor PM5 (missense, not a PTC variant under ENIGMA PM5_PTC rules) is met.	cspec
PM1	N/A	ENIGMA BRCA1/2 specification v1.2 marks PM1 as Not Applicable; captured by other domain analysis criteria within the specification.	cspec
PM2	Met	NM_007294.4:c.2531G>C is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	PM3 applies to recessive disorders where a pathogenic variant is detected in trans with another pathogenic variant. BRCA1-associated disease is autosomal dominant; PM3 is trivially not applicable in this context.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. NM_007294.4:c.2531G>C is a missense substitution and does not alter protein length.
PM5	N/A	ENIGMA PM5 is repurposed for PTC (protein termination codon) variants where a different proven pathogenic PTC variant has been observed in the same exon. c.2531G>C is a missense substitution (p.Ser844Thr), not a PTC. The classic same-residue missense PM5 is not applied under the ENIGMA BRCA1 framework.	pm5_candidates cspec
PM6	N/A	ENIGMA BRCA1/2 specification v1.2 marks PM6 as Not Applicable.	cspec
PP1	Not met	No co-segregation data are available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with an LR ≥ 2.08 (Supporting), ≥ 4.3 (Moderate), or ≥ 18.7 (Strong).	cspec
PP2	N/A	ENIGMA BRCA1/2 specification v1.2 marks PP2 as Not Applicable.	cspec
PP3	Not met	ENIGMA PP3 requires either (a) BayesDel no-AF ≥ 0.28 for missense variants inside a clinically important functional domain, or (b) SpliceAI ≥ 0.2 for any missense/silent/intronic variant. p.Ser844Thr is outside all ENIGMA-defined functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI max delta = 0.00. BayesDel no-AF = -0.204893 does not meet the ≥ 0.28 threshold. Neither pathway to PP3 is satisfied.	spliceai bayesdel revel cspec
PP4	Not met	ENIGMA PP4 is based on the Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio model. c.2531G>C was searched in the BRCA1 clinical_history_LR table (1,329 rows) and was not found. The only nearby BRCA1 variant in the table was c.2633C>T, which is a different variant. No clinical history LR is available for c.2531G>C.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
PP5	N/A	ENIGMA BRCA1/2 specification v1.2 marks PP5 as Not Applicable; reputable source reports are not used as independent evidence under this framework.	cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% (FAF > 0.001) in gnomAD v2.1 and/or v3.1 non-cancer, non-founder populations. The variant is absent from gnomAD in all datasets (v2.1, v4.1, Canada).	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	ENIGMA BS1_Strong requires FAF > 0.01% and BS1_Supporting requires FAF > 0.002% in gnomAD. The variant is absent from gnomAD in all datasets.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	ENIGMA BS2 requires observation of the variant in the absence of Fanconi Anemia phenotype features, scored via the points system in Specifications Table 8. No proband observation data are available for c.2531G>C.	cspec
BS3	Not met	c.2531G>C (p.Ser844Thr) is not listed in the ENIGMA Table 9 curated functional assay results for benign functional evidence. It was also absent from ST4, ST5, and Parsons et al. 2019 functional datasets. No variant-specific evidence of normal protein function is available.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BS4	Not met	No segregation data demonstrating lack of segregation with disease are available for c.2531G>C.	cspec
BP1	Met	c.2531G>C (p.Ser844Thr) is a missense substitution located at residue 844, which is outside all ENIGMA-defined clinically important functional domains for BRCA1 (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1). This meets ENIGMA BP1_Strong.	spliceai cspec
BP2	N/A	ENIGMA BRCA1/2 specification v1.2 marks BP2 as Not Applicable.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in a repetitive region without a known function. Not applicable to this missense substitution variant.
BP4	N/A	ENIGMA BP4_Supporting applies only to missense variants inside a (potentially) clinically important functional domain with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1. p.Ser844Thr is outside all ENIGMA functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). The precondition of domain localization is not met.	bayesdel spliceai cspec
BP5	Not met	ENIGMA BP5 is based on the Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio model for benign direction. c.2531G>C was not found in the BRCA1 clinical_history_LR table (1,329 rows). No LR is available to support BP5.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
BP6	N/A	ENIGMA BRCA1/2 specification v1.2 marks BP6 as Not Applicable.	cspec
BP7	N/A	ENIGMA BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile. ENIGMA BP7_Supporting applies to silent variants inside a functional domain or intronic variants outside conserved splice positions. c.2531G>C is a missense variant with no mRNA splicing data available.	cspec

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