Variant classification summary

NM_007294.4:c.67G>A

BRCA1 · NP_009225.1:p.(Glu23Lys) · NM_007294.4

GRCh37: chr17:41276047 C>T · GRCh38: chr17:43124030 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

BS3_Strong BP4_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Glu23Lys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.67G>A (p.Glu23Lys, E23K) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with a single submitter interpretation of uncertain significance.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in population databases.

3

In a calibrated BRCA1 functional study, this variant showed no functional impact and BRCA1 expert-panel materials assign BS3_Strong for c.67G>A.

4

Available computational evidence does not support a damaging effect under the BRCA1 ENIGMA rule: BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the threshold of 0.1; REVEL is 0.734 but is not the governing BRCA1 VCEP threshold for PP3/BP4.

Final determination: BS3_Strong together with BP4_Supporting meets the ENIGMA Table 3 rule for a Likely Benign classification.

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	This variant is a missense substitution, p.(Glu23Lys), and does not fall into the BRCA1 null-variant categories used for PVS1. Available evidence does not support a truncating or canonical splice-site mechanism for this variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No confirmed pathogenic or likely pathogenic comparator producing the same amino acid change was identified in the reviewed materials, so PS1 was not assessed from the currently available evidence.	cspec
PS2	N/A	This BRCA1 specification marks PS2 as not applicable.	cspec
PS3	Not met	Available functional evidence does not support a damaging effect. In the reviewed BRCA1 functional datasets, this variant was reported as having no functional impact rather than an abnormal function pattern.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399
PS4	Not assessed	No case-control study or quantified enrichment data showing that this variant is significantly more common in affected individuals than controls were identified, so PS4 was not assessed.	cspec clinvar
PM1	N/A	This BRCA1 specification marks PM1 as not applicable for variant classification.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is consistent with rarity. However, the reviewed materials did not provide the full BRCA1 VCEP PM2 control and coverage confirmation required to assign PM2_Supporting with confidence, so PM2 was not assessed in this pass.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified that this variant has been observed in the biallelic Fanconi anemia context required for BRCA1 PM3 scoring, so PM3 was not assessed.	cspec
PM4	N/A	This BRCA1 specification marks PM4 as not applicable.	cspec
PM5	N/A	For BRCA1 in this framework, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison. Because c.67G>A is a missense variant, PM5 is not applicable here.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This BRCA1 specification marks PM6 as not applicable.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec clinvar
PP2	N/A	This BRCA1 specification marks PP2 as not applicable.	cspec
PP3	Not met	This missense variant lies in the BRCA1 RING domain, but the computational thresholds for PP3 are not met. BayesDel no-AF is 0.076, which is below the BRCA1 PP3 threshold of 0.28, and SpliceAI is 0.00, which is below the splice threshold of 0.2. REVEL is 0.734, but the BRCA1 VCEP rule uses BayesDel and SpliceAI for PP3/BP4 adjudication.	cspec bayesdel spliceai revel vcep_appendices_v1_2_2024_11_18
PP4	Not assessed	No variant-specific BRCA1 clinical-history likelihood ratio meeting PP4 thresholds was identified in the reviewed materials, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
PP5	N/A	This BRCA1 specification marks PP5 as not applicable.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA1 BA1 threshold of filter allele frequency greater than 0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA1 BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying observations in unaffected individuals meeting the BRCA1 BS2 point-based framework were identified, so BS2 was not assessed.	cspec
BS3	Met	In a calibrated BRCA1 functional study, this variant showed protein function similar to benign control variants, and BRCA1 expert-panel materials assign BS3_Strong. Supplementary functional data list c.67G>A as having no functional impact.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec
BP1	Not met	BP1_Strong requires a missense or similar variant outside a clinically important BRCA1 functional domain with no splice effect. This variant affects codon 23 in the BRCA1 RING domain, so BP1 is not met.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP2	N/A	This BRCA1 specification marks BP2 as not applicable.	cspec
BP3	N/A	This BRCA1 specification marks BP3 as not applicable.	cspec
BP4	Met	This missense variant lies in the BRCA1 RING domain and shows no predicted damaging effect under the BRCA1 computational rule. BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the splice threshold of 0.1, supporting BP4_Supporting.	cspec bayesdel spliceai vcep_appendices_v1_2_2024_11_18
BP5	Not assessed	No variant-specific BRCA1 clinical-history likelihood ratio at or below the BP5 thresholds was identified in the reviewed materials, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
BP6	N/A	This BRCA1 specification marks BP6 as not applicable.	cspec
BP7	N/A	BP7 in this BRCA1 specification is used for silent or intronic variants, and this variant is a missense substitution, so BP7 is not applicable.	cspec

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