Variant classification summary

NM_000059.3:c.5946del

BRCA2 · NP_000050.2:p.(Ser1982ArgfsTer22) · NM_000059.3

GRCh37: chr13:32914437 GT>G · GRCh38: chr13:32340300 GT>G

Gene: BRCA2 Transcript: NM_000059.3

Final call

Pathogenic

PVS1_VeryStrong PM5_Strong PP4_Strong PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Ser1982ArgfsTer22)

gnomAD AF

0.00013941574270174079 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.5946del (p.(Ser1982ArgfsTer22)) variant has been observed in somatic cancers in COSMIC (COSV66447676, n=10) and has been reported in ClinVar as pathogenic with expert-panel review by the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.

2

This variant is present in population databases, including gnomAD v2.1 at AF 0.000276509 (78/282088 alleles) and gnomAD v4.1 at AF 0.000139416 (225/1613878 alleles), with highest frequency in the Ashkenazi Jewish population; therefore it is not absent from controls and does not meet PM2.

3

Clinical-history evidence supports pathogenicity: in the BRCA2 likelihood-ratio dataset, c.5946delT has an LR of 31.79 from 149 probands, exceeding the ENIGMA PP4_Strong threshold of 18.7.

4

Computational and predicted consequence data show a frameshift leading to p.(Ser1982ArgfsTer22), while SpliceAI predicts no additional splice alteration (max delta 0.00); under the BRCA2 ENIGMA exon-specific truncating-variant framework, exon 11 supports PVS1 and PM5_Strong for this protein-truncating variant.

Final determination: Pathogenic based on 1 very strong pathogenic criterion (PVS1) and at least 1 strong pathogenic criterion (PM5; PP4 also strong), which meets the ENIGMA BRCA1/2 Table 3 pathogenic combination rule.

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	Met	This variant is a frameshift deletion predicted to cause p.(Ser1982ArgfsTer22) / p.(S1982Rfs*22). BRCA2 loss of function is an established disease mechanism, and the BRCA2 ENIGMA Table 4 exon 11 rule assigns PVS1 for truncating variants in this exon, supporting PVS1 at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	This criterion is defined for same amino-acid substitutions or equivalent splicing effects relative to a previously classified variant. This variant is a frameshift deletion, so PS1 is not applicable.	cspec
PS2	N/A	De novo evidence is not part of the applicable BRCA2 ENIGMA framework for this variant assessment, and no validated de novo data were identified.	cspec
PS3	Not assessed	No calibrated variant-specific functional assay result for c.5946del was identified from the BRCA2 ENIGMA functional evidence sources reviewed. General BRCA2 loss-of-function literature supports the disease mechanism, but it does not provide a variant-specific PS3 assignment here.	vcep_specifications_table9_v1_2_2024_11_18 oncokb PMID:10570174 PMID:11239455
PS4	Not assessed	This founder variant has been widely reported in affected individuals, but no reviewed case-control analysis with explicit odds ratio meeting the BRCA2 ENIGMA PS4 requirement was identified here. Available observation data therefore do not support a direct PS4 assignment in this pass.	cspec clinvar PMID:10417300 PMID:11466700
PM1	N/A	PM1 is not applicable in the BRCA2 ENIGMA framework for this truncating variant assessment.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.000276509 (78/282088 alleles) and in gnomAD v4.1 at AF 0.000139416 (225/1613878 alleles), so the BRCA2 ENIGMA PM2 requirement for absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. PM3 was therefore not assessed.	cspec
PM4	N/A	PM4 is not applicable in the BRCA2 ENIGMA framework for this truncating variant assessment.	cspec
PM5	Met	This variant creates a premature termination codon in BRCA2 exon 11. In the BRCA2 ENIGMA exon-level Table 4, exon 11 is designated PM5_Strong for PTC variants, indicating that different proven pathogenic truncating variants have been observed in this exon and supporting PM5 at strong strength.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	De novo evidence is not part of the applicable BRCA2 ENIGMA framework for this variant assessment, and no validated de novo data were used here.	cspec
PP1	Not assessed	No quantitative co-segregation likelihood ratio meeting BRCA2 ENIGMA PP1 thresholds was identified for this variant. Segregation evidence was therefore not assessed.	cspec PMID:14559878
PP2	N/A	PP2 is not applicable in the BRCA2 ENIGMA framework.	cspec
PP3	N/A	The BRCA2 ENIGMA PP3 rule is for missense, in-frame, or non-canonical splicing contexts. This variant is a frameshift deletion already evaluated under the truncating-variant framework, so PP3 is not applicable.	cspec spliceai
PP4	Met	In the BRCA2 clinical-history likelihood-ratio dataset, this variant is listed as c.5946delT with LR 31.79 from 149 probands. This exceeds the BRCA2 ENIGMA PP4_Strong threshold of 18.7, supporting PP4 at strong strength.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The BRCA2 ENIGMA BA1 threshold requires non-founder population filter allele frequency greater than 0.001. The observed grpmax founder filter allele frequency is 5.39e-05 in gnomAD v2.1 and 2.154e-05 in gnomAD v4.1, both below 0.001, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The BRCA2 ENIGMA BS1 rule is based on non-founder population filter allele frequency. Although this founder variant is enriched in the Ashkenazi Jewish population, the reviewed data do not show a qualifying non-founder FAF above 0.00002 or 0.0001, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No point-based BRCA2 ENIGMA BS2 evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the framework rules. BS2 was therefore not assessed.	cspec
BS3	Not assessed	No calibrated benign functional assay result for c.5946del was identified in the reviewed BRCA2 functional evidence sources. BS3 was therefore not assessed.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative non-segregation likelihood ratio meeting BRCA2 ENIGMA BS4 thresholds was identified for this variant. BS4 was therefore not assessed.	cspec PMID:14559878
BP1	N/A	The BRCA2 ENIGMA BP1 rule applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect. This variant is a frameshift deletion, so BP1 is not applicable.	cspec
BP2	N/A	BP2 is not applicable in the BRCA2 ENIGMA framework.	cspec
BP3	N/A	BP3 is not applicable in the BRCA2 ENIGMA framework.	cspec
BP4	N/A	The BRCA2 ENIGMA BP4 rule applies to selected missense, in-frame, silent, or intronic variants with low predicted impact. This variant is a frameshift deletion, so BP4 is not applicable, even though SpliceAI does not predict an additional splice effect (max delta 0.00).	cspec spliceai
BP5	Not met	The variant-specific BRCA2 clinical-history likelihood ratio is 31.79, which is in the pathogenic direction and well above the BP5 thresholds of 0.48, 0.23, 0.05, and 0.00285. BP5 is therefore not met.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not applicable in the BRCA2 ENIGMA framework.	cspec
BP7	N/A	The BRCA2 ENIGMA BP7 rule applies to silent or intronic variants and selected RNA-only contexts. This variant is a frameshift deletion, so BP7 is not applicable.	cspec spliceai

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