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BRCA1
Final classification
Likely Benign
BRCA1 c.2531G>C · p.Ser844Thr
BRCA1

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).

Gene
BRCA1
Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.2531G>C
Consequence
N/A
GRCh38
chr17:43093000 C>G
GRCh37
chr17:41245017 C>G
Basis ENIGMA BRCA1/BRCA2 v1.2 Table 3 point system for conflicting evidence. Only two criteria met: PM2_Supporting (+1 pathogenic point) and BP1_Strong (-4 benign points). Total = -3, which falls in the Likely Benign range (-6 to -2).
ENIGMA BRCA1/BRCA2 v1.2 Table 3 point system for conflicting evidence. Only two criteria met: PM2_Supporting (+1 pathogenic point) and BP1_Strong (-4 benign points). Total = -3, which falls in the Likely Benign range (-6 to -2).
Classification rationale
PM2 BP1 Likely Benign
BRCA1 c.2531G>C

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).1 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.2 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.3 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).4 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.5

PM2 + BP1 Likely Benign
3 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
4 vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting review Pathogenic
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.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.
BP1 strong Benign
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.
Variant is at residue 844outside RING (2-101)coiled-coil (1391-1424)
Assessed · not applied
Pathogenic
PS1 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.
PS3 c.2531G>C (p.Ser844Thr) is not listed in the ENIGMA Table 9 curated functional assay results.
PS4 No case-control data demonstrating significantly increased prevalence in affected individuals versus controls (p≤0.05, OR≥4) are available for this variant.
PP1 No co-segregation data are available for this variant.
PP3 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.
PP4 ENIGMA PP4 is based on the Li et al.
Benign
BA1 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.
BS1 ENIGMA BS1_Strong requires FAF > 0.01% and BS1_Supporting requires FAF > 0.002% in gnomAD.
BS2 ENIGMA BS2 requires observation of the variant in the absence of Fanconi Anemia phenotype features, scored via the points system in Specifications Table 8.
BS3 c.2531G>C (p.Ser844Thr) is not listed in the ENIGMA Table 9 curated functional assay results for benign functional evidence.
BS4 No segregation data demonstrating lack of segregation with disease are available for c.2531G>C.
BP5 ENIGMA BP5 is based on the Li et al.
N/A · 14 PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.564. BayesDel score = -0.204893.
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 5 PMIDs not cited in assessment
15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR
19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR