c.4935G>C (p.Arg1645Ser) is a missense variant in BRCA1 exon 15, located at amino acid position 1645, five residues N-terminal to the BRCT domain (aa 1650-1857).1 ENIGMA BRCA1 VCEP Table 9 assigns BS3 (Strong) to this variant based on two calibrated functional studies demonstrating protein function indistinguishable from benign control variants (Findlay 2018, PMID:30209399; Fernandes 2019, PMID:30765603).2 ENIGMA BP1_Strong applies because the variant is a missense substitution located outside all clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857) with no predicted splicing impact (SpliceAI max delta 0.02).3 PM2_Supporting is met because the variant is absent from gnomAD v2.1 and v4.1 in outbred populations.4 Per ENIGMA Table 3 combining rules, two Strong Benign criteria (BS3 + BP1) meet the threshold for Benign classification. The single Supporting Pathogenic criterion (PM2) does not alter the classification.5 Final classification: Benign.
BRCA1
Final classification
Benign
BRCA1 c.4935G>C · p.Arg1645Ser
BRCA1
c.4935G>C (p.Arg1645Ser) is a missense variant in BRCA1 exon 15, located at amino acid position 1645, five residues N-terminal to the BRCT domain (aa 1650-1857).
ENIGMA BRCA1/BRCA2 v1.2 Table 3 conflicting-evidence point system: BS3 Strong (-4) + BP1 Strong (-4) + PM2 Supporting (+1) = -7, which meets the Benign threshold (<= -7). The two Strong benign criteria also independently satisfy the ENIGMA Table 3 benign combination rule (2 Strong Benign -> Benign).
Classification rationale
PM2
BS3BP1
Benign
BRCA1 c.4935G>C
PM2 + BS3 + BP1
→
Benign
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
Variant is absent from gnomAD v2.1 (exome, non-cancer) and gnomAD v4.1 (non-cancer). Per ENIGMA v1.2, PM2_Supporting applies when a variant is absent from controls in outbred populations (read depth >=25 assumed per pipeline).
Absent from gnomAD v2.1Absent from gnomAD v4.1
✓
BS3
strong
Benign
ENIGMA Table 9 assigns BS3 (Strong) to c.4935G>C (p.Arg1645Ser). Two calibrated functional studies demonstrate protein function similar to benign control variants: Findlay et al. 2018 (PMID:30209399, saturation genome editing, classification: FUNC) and Fernandes et al. 2019 (PMID:30765603, BRCT domain functional assay, classification: Not Pathogenic). ST4 confirms no functional impact with FUNC classification.
ENIGMA Table 9: c.4935G>C BS3 StrongFindlay 2018: saturation genome editingFUNC (no functional impact)
✓
BP1
strong
Benign
ENIGMA BP1_Strong applies to missense variants located outside a clinically important functional domain with no splicing predicted. Arg1645 (position 1645) lies outside all three BRCA1 functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI max delta is 0.02 (<=0.1), predicting no splicing impact.
Position 1645 is outside all BRCA1 functional domains (RING 2-101coiled-coil 1391-1424BRCT 1650-1857)
Assessed · not applied
Pathogenic
PS1
No pathogenic missense variant has been established at residue Arg1645.
PS3
ENIGMA Table 9 assigns BS3 (Strong) to c.4935G>C based on two calibrated functional studies (Findlay 2018 PMID:30209399, Fernandes 2019 PMID:30765603) showing protein function similar to benign control variants.
PS4
No case-control study with odds ratio and p-value is available for this variant.
PP1
No co-segregation data or likelihood ratio analysis is available for this variant.
PP3
PP3 for missense variants requires location inside a clinically important functional domain AND BayesDel no-AF score >=0.28.
PP4
Variant is not present in the Li et al.
Benign
BA1
Variant is absent from gnomAD v2.1 and v4.1.
BS1
Variant is absent from gnomAD v2.1 and v4.1.
BS2
No proband-level co-occurrence data or data on observation in healthy adults without Fanconi Anemia phenotype is available for this variant.
BS4
No segregation data or likelihood ratio analysis is available for this variant.
BP4
ENIGMA BP4 for missense variants explicitly requires location inside a clinically important functional domain with BayesDel <=0.15 and SpliceAI <=0.1.
BP5
Variant is not present in the Li et al.
BP7
No mRNA splicing assay data is available for this variant.
N/A · 9
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 55321)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.602. BayesDel score = -0.0818436.
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.
COSMIC
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.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
Accurate classification of BRCA1 variants with saturation genome editing.
Searched
c.4935G>Cp.Arg1645SerR1645S
Found
Saturation genome editing of BRCA1 exon 15 (BRCT domain region). c.4935G>C (p.Arg1645Ser) was classified as FUNC (functional, no damaging effect), indicating protein function similar to benign control variants.
Variant
✓ Names this variant
Applied to
→BS3 supports · met
Why
ENIGMA Table 9 cites this study as source of BS3 Strong evidence; variant shows no functional impact in saturation genome editing assay.
Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation.
Searched
c.4935G>Cp.Arg1645SerR1645S
Found
Functional characterization of amino acid substitutions in the BRCT domains of BRCA1. c.4935G>C (p.Arg1645Ser) was classified as Not Pathogenic based on integrated functional assay data.
Variant
✓ Names this variant
Applied to
→BS3 supports · met
Why
ENIGMA Table 9 cites this study as second source of BS3 Strong evidence; variant classified as Not Pathogenic.
Sources & reference links
9Sources
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
29176636 ↗
Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
16284991 ↗
BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR