The BRCA1 c.5509T>G (p.Trp1837Gly; W1837G) variant has been reported in ClinVar with an expert-panel Pathogenic classification by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, and OncoKB classifies the variant as Likely Oncogenic with likely loss-of-function biological effect.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed population frequency of 0 in the available population datasets and supporting PM2_Supporting under the ENIGMA framework.2 ENIGMA curated functional data for c.5509T>G are discordant across calibrated studies, so neither PS3 nor BS3 is met for this variant.3 The variant lies in the BRCA1 BRCT repeats and has an ENIGMA supplementary BayesDel no-AF score of approximately 0.533, above the PP3 threshold of ≥0.28, while SpliceAI predicts no significant splice impact with a max delta score of 0.00.4 The BRCA1 clinical-history likelihood-ratio table reports c.5509T>G in 2 probands with LR 8.0617, exceeding the PP4_Moderate threshold of LR ≥4.3 and falling below the PP4_Strong threshold of LR ≥18.7.5
Final classification
Uncertain Significance
PM2PP3PP4PP5
BRCA1
c.5509T>G
p.Trp1837Gly
This variant
The BRCA1 c.5509T>G (p.Trp1837Gly; W1837G) variant has been reported in ClinVar with an expert-panel Pathogenic classification by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, and OncoKB classifies the variant as Likely Oncogenic with likely loss-of-function biological effect.
Official ENIGMA BRCA1/BRCA2 v1.2 Table 3 final-classification framework was used. Applied pathogenic evidence comprises PP4_Moderate plus PM2_Supporting, PP3_Supporting, and PP5_Supporting; no benign criteria are applied. This combination does not meet ENIGMA Table 3 thresholds for Pathogenic or Likely Pathogenic, and no benign classification threshold is met.
Classification rationale
PM2PP3PP4PP5
Uncertain Significance
BRCA1 c.5509T>G
PM2 + PP3 + PP4 + PP5
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
4
vcep_appendices_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18spliceai ↗cspec ↗
5
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗cspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed population frequency is 0 in the available gnomAD datasets, which is below the ENIGMA PM2_Supporting absent-from-controls threshold.
gnomAD v2.1 search status: absent.gnomAD v4.1 search status: absent.
PP3
supporting
Pathogenic
This missense variant lies in the BRCA1 BRCT repeats, a clinically important functional domain spanning amino acids 1650-1857. The BayesDel no-AF score reported in ENIGMA supplementary bioinformatic data is approximately 0.533, which is above the pathogenic computational threshold of ≥0.28, while SpliceAI max delta score is 0.00; this supports PP3 for predicted protein impact rather than splicing impact.
BRCA1 p.Trp1837Gly is within the BRCT repeats.ENIGMA ST13 lists c.5509T>G p.Trp1837Gly in BRCT repeats with BayesDel no-AF approximately 0.533.SpliceAI max delta score is 0.00
PP4
moderate
Pathogenic
The BRCA1 clinical-history likelihood-ratio table reports this variant in 2 probands with LR 8.0617. This is above the PP4_Moderate threshold of LR ≥4.3 and below the PP4_Strong threshold of LR ≥18.7, supporting PP4 at Moderate strength.
PMID:31853058 BRCA1 clinical-history LR table row for c.5509T>G: N_Probands=2LR=8.061718376504666.
Assessed · not applied
· 10 not met · 5 not assessed
Pathogenic
PVS1
This BRCA1 variant is a missense substitution, p.(Trp1837Gly), and does not create a nonsense, frameshift, initiation-codon, exon-level deletion, or canonical ±1,2 splice variant.
PS1
No previously classified pathogenic variant producing the same Trp1837Gly amino acid change, or the same predicted splicing impact, was identified.
PS3
Calibrated functional evidence for c.5509T>G is discordant: two calibrated studies reported a functional effect similar to pathogenic controls, while another reported an intermediate/partial result.
PS4
No case-control evidence was identified showing that this variant is significantly enriched in affected individuals with p ≤0.05 and odds ratio ≥4 with the lower confidence interval excluding 2.0.
PM3
No Fanconi anemia phenotype or qualifying biallelic BRCA1 co-occurrence evidence was identified.
PP1
No quantitative co-segregation evidence was identified for this variant.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1.
BS2
No qualifying observation in individuals without features of BRCA1/2-related Fanconi anemia was identified.
BS3
Calibrated functional evidence for c.5509T>G is discordant and does not consistently show no damaging effect.
BS4
No quantitative lack-of-segregation evidence was identified for this variant.
BP1
BP1_Strong applies to missense, silent, or in-frame variants outside clinically important functional domains with no predicted splicing effect.
BP4
BP4 requires no predicted protein or splicing impact for an in-domain missense variant, including BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
BP5
The BRCA1 clinical-history likelihood-ratio table reports LR 8.0617 for this variant, which is above the pathogenic-direction PP4_Moderate threshold and not below the BP5 supporting threshold of LR ≤0.48.
BP7
BP7 is intended for specific silent, intronic, out-of-domain missense/in-frame, or RNA-assay contexts.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
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.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
BRCA1 clinical-history LR table row for c.5509T>G: N_Probands=2 LR=8.061718376504666.
Applied to
→PP4
moderate
Sources & reference links