Variant classification summary

NM_000059.4:c.7992T>A

BRCA2 · NP_000050.3:p.(Ile2664=) · NM_000059.4

GRCh37: chr13:32937331 T>A · GRCh38: chr13:32363194 T>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

BS1_Supporting BP4_Supporting BP6_Supporting BP7_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile2664=)

gnomAD AF

3.6562618131340363e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.7992T>A (p.Ile2664=) variant has been reported in ClinVar, including a likely benign expert panel classification from ENIGMA and multiple likely benign clinical laboratory submissions.

2

In population databases, the variant is present at low frequency; in gnomAD v2.1 the grpmax filter allele frequency is 3.433e-05, which exceeds the BRCA2 ENIGMA BS1 Supporting threshold of 2.0e-05, and gnomAD v4.1 shows a consistent low-frequency signal with grpmax filter allele frequency 3.666e-05.

3

SpliceAI predicts no significant splice effect with a maximum delta score of 0.02, which is below the BRCA2 ENIGMA BP4/BP7 threshold of 0.1 and below the PP3 threshold of 0.2, supporting BP4 and BP7 rather than a deleterious splicing prediction.

Final determination: Likely benign based on multiple supporting benign criteria under ENIGMA BRCA1/BRCA2 Table 3.

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 synonymous variant does not create a premature termination codon, frameshift, or canonical ±1,2 splice-site change, and no RNA assay evidence was identified to support a PVS1(RNA) application.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not assessed	No verified pathogenic or likely pathogenic comparator with the same predicted protein or splicing consequence was identified from the available evidence.	cspec
PS2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay result supporting a damaging effect was identified for c.7992T>A.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS4	Not assessed	No case-control enrichment data meeting the BRCA2 ENIGMA PS4 thresholds were identified for this variant.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	This criterion is not applied in the BRCA2 ENIGMA specification.	cspec
PM2	Not met	This variant is present in population databases and therefore is not absent from controls. In gnomAD v2.1 the total allele frequency is 3.19e-05 (8/250460) and in gnomAD v4.1 the total allele frequency is 3.66e-05 (59/1613670).	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for occurrence with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia.	cspec
PM4	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	In the BRCA2 ENIGMA framework, PM5 is repurposed for protein-truncating variant logic and does not apply to this synonymous substitution.	pm5_candidates cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant.	cspec
PP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP3	Not met	Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, which is below the BRCA2 ENIGMA PP3 threshold of 0.2. REVEL and BayesDel scores were not available for this synonymous change.	spliceai cspec
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting BRCA2 ENIGMA PP4 thresholds was identified in the available data.	vcep_pmid_31853058_brca2_clinical_history_lr cspec
PP5	N/A	This criterion is not used in current ACMG/AMP-based BRCA2 ENIGMA classification.	cspec
BA1	Not met	The observed population frequency is below the BRCA2 ENIGMA BA1 threshold. In gnomAD v2.1, grpmax filter allele frequency is 3.433e-05, which is below the BA1 cutoff of 0.001.	gnomad_v2 cspec
BS1	Met	This variant meets BRCA2 ENIGMA BS1 at supporting strength because the gnomAD v2.1 grpmax filter allele frequency is 3.433e-05, which is above the BS1 Supporting threshold of 2.0e-05 and at or below the upper BS1 boundary of 1.0e-04. The highest observed population is European (non-Finnish).	gnomad_v2 cspec
BS2	Not assessed	No point-based evidence was identified to support BS2 under the BRCA2 ENIGMA Fanconi-anemia-related framework.	cspec
BS3	Not assessed	No variant-specific calibrated functional assay result showing no damaging effect was identified for c.7992T>A.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio meeting BRCA2 ENIGMA BS4 thresholds was identified for this variant.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Not met	This synonymous variant is located at codon 2664 within the BRCA2 DNA-binding domain (aa 2481-3186), so it does not meet the BRCA2 ENIGMA BP1 rule for silent or missense variants outside clinically important functional domains.	cspec
BP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP4	Met	This synonymous variant lies within the BRCA2 DNA-binding domain and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02, which is below the BRCA2 ENIGMA BP4 threshold of 0.1. REVEL and BayesDel scores were not available, but they are not required for this silent-variant BP4 rule.	spliceai cspec
BP5	Not assessed	No variant-specific clinical-history likelihood ratio meeting BRCA2 ENIGMA BP5 thresholds was identified in the available data.	vcep_pmid_31853058_brca2_clinical_history_lr cspec
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.	cspec clinvar
BP7	Met	This synonymous variant is located within the BRCA2 DNA-binding domain and also meets BP4 because SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. Under the BRCA2 ENIGMA rule, a silent variant inside a clinically important functional domain can receive BP7 at supporting strength when BP4 is met.	spliceai cspec

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