Variant classification summary

NM_007294.4:c.5509T>G

BRCA1 · NP_009225.1:p.(Trp1837Gly) · NM_007294.4

GRCh37: chr17:41197778 A>C · GRCh38: chr17:43045761 A>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Trp1837Gly)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

ENIGMA curated functional data for c.5509T>G are discordant across calibrated studies, so neither PS3 nor BS3 is met for this variant.

4

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.

5

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.

Final determination: One moderate and three supporting pathogenic criteria, with no benign criteria, do not meet ENIGMA BRCA1/BRCA2 Table 3 criteria-combination thresholds for Pathogenic or Likely Pathogenic classification; the variant is classified as Uncertain Significance.

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	Not met	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. Although BRCA1 loss of function is an established disease mechanism, the null-variant PVS1 rule is not met for this missense change.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously classified pathogenic variant producing the same Trp1837Gly amino acid change, or the same predicted splicing impact, was identified. Other substitutions at this codon are not sufficient for PS1 because they do not produce the same amino acid change.	cspec vcep_specifications_table9_v1_2_2024_11_18 spliceai
PS2	N/A	De novo occurrence is not an applicable ENIGMA BRCA1/2 criterion for this framework.	cspec
PS3	Not met	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. ENIGMA Table 9 assigns no PS3 code for this variant, so PS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	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. Therefore PS4 was not assessed as met.	cspec clinvar
PM1	N/A	PM1 is not used as an applicable standalone criterion under the ENIGMA BRCA1/2 specification. The BRCT domain location is instead incorporated into the ENIGMA PP3/BP4/BP1 bioinformatic framework.	cspec vcep_appendices_v1_2_2024_11_18
PM2	Met	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 gnomad_v4 cspec
PM3	Not assessed	No Fanconi anemia phenotype or qualifying biallelic BRCA1 co-occurrence evidence was identified. PM3 was therefore not assessed as met.	cspec
PM4	N/A	PM4 is not applicable under the ENIGMA BRCA1/2 specification for this variant interpretation framework.	cspec
PM5	N/A	ENIGMA PM5 is applied to protein termination codon variants in exons where a different proven pathogenic protein termination codon variant has been observed. This variant is missense, p.(Trp1837Gly), so PM5_PTC is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo occurrence is not an applicable ENIGMA BRCA1/2 criterion for this framework.	cspec
PP1	Not assessed	No quantitative co-segregation evidence was identified for this variant. PP1 requires a segregation likelihood ratio of at least 2.08 for supporting strength, and no such LR was available.	cspec
PP2	N/A	PP2 is not applicable under the ENIGMA BRCA1/2 specification.	cspec
PP3	Met	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.	cspec vcep_supplementarytables_v1_2_2024_11_18 spliceai vcep_appendices_v1_2_2024_11_18
PP4	Met	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.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed population frequency is 0, which is below the ENIGMA BA1 threshold of FAF >0.1% (>0.001), so BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed population frequency is 0, which is below both ENIGMA BS1 thresholds: >0.002% (>0.00002) for supporting and >0.01% (>0.0001) for strong, so BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying observation in individuals without features of BRCA1/2-related Fanconi anemia was identified. BS2 requires point-based unaffected-carrier evidence, and no such evidence was available.	cspec
BS3	Not met	Calibrated functional evidence for c.5509T>G is discordant and does not consistently show no damaging effect. ENIGMA Table 9 assigns no BS3 code for this variant, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant. BS4 requires a segregation likelihood ratio of ≤0.48 for supporting benign evidence, and no such LR was available.	cspec
BP1	Not met	BP1_Strong applies to missense, silent, or in-frame variants outside clinically important functional domains with no predicted splicing effect. This variant is inside the BRCA1 BRCT repeats, a clinically important functional domain, so BP1 is not met despite SpliceAI max delta score 0.00.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	BP2 is not applicable under the ENIGMA BRCA1/2 specification.	cspec
BP3	N/A	BP3 is not applicable under the ENIGMA BRCA1/2 specification.	cspec
BP4	Not met	BP4 requires no predicted protein or splicing impact for an in-domain missense variant, including BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. Although SpliceAI max delta score is 0.00, the ENIGMA supplementary BayesDel no-AF score is approximately 0.533, which is above the benign threshold of ≤0.15, so BP4 is not met.	cspec vcep_supplementarytables_v1_2_2024_11_18 spliceai
BP5	Not met	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. Therefore BP5 is not met.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not applicable under the ENIGMA BRCA1/2 specification; benign database assertions are not used as standalone evidence.	cspec
BP7	Not met	BP7 is intended for specific silent, intronic, out-of-domain missense/in-frame, or RNA-assay contexts. This variant is an in-domain BRCA1 BRCT missense variant, and no qualifying benign RNA evidence or BS3 evidence was identified; therefore BP7 is not met.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18

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