NM_000059.4:c.2818C>T

BRCA2 · NP_000050.3:p.(Gln940Ter) · NM_000059.4

GRCh37: chr13:32911310 C>T · GRCh38: chr13:32337173 C>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gln940Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.2818C>T (p.Gln940Ter) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.

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

This nonsense variant truncates BRCA2 at codon 940 in exon 11, where the ENIGMA BRCA2 specification assigns PVS1 and PM5_Strong (PTC) for protein-truncating variants, consistent with BRCA2 loss of function as an established disease mechanism.

BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 from 3 probands, meeting the ENIGMA threshold for PP4_Supporting.

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, which does not reach the BRCA2 PP3 protein-impact threshold of 0.30.

Final determination: Pathogenic based on 1 Very Strong criterion (PVS1) and 1 Strong criterion (PM5), which meets the ENIGMA BRCA1/BRCA2 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 nonsense change, NM_000059.4:c.2818C>T (p.Gln940Ter), predicted to truncate BRCA2 early in exon 11. Germline loss of function is an established BRCA2 disease mechanism, and the ENIGMA BRCA2 exon-level PVS1 table assigns exon 11 protein-truncating variants to PVS1.	cspec vcep_specifications_table4_v1_2_2024_11_18 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This variant is a nonsense change, and no same-amino-acid missense comparator or same-splicing comparator evidence was identified for PS1 under the BRCA2 specification.	cspec
PS2	N/A	No de novo framework is used for this BRCA2 VCEP assessment, and no confirmed de novo evidence was identified.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay result for c.2818C>T was identified in the ENIGMA BRCA1/2 functional assay table. General BRCA2 loss-of-function biology does not by itself provide criterion-ready PS3 evidence for this specific variant.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not met	This variant has been reported in ClinVar and has been observed once in COSMIC, but no case-control study showing significantly increased prevalence in affected individuals with p-value 0.05 or less and odds ratio 4 or greater was identified. These observations do not meet BRCA2 PS4 requirements.	clinvar cspec
PM1	N/A	PM1 is not used in this BRCA2 VCEP framework for this variant context.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations. Under the BRCA2 specification, absence from gnomAD supports PM2_Supporting.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia. PM3 was therefore not assessed.	cspec
PM4	N/A	PM4 is not used in this BRCA2 VCEP framework.	cspec
PM5	Met	In the BRCA2 ENIGMA specification, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This nonsense variant lies in exon 11, and the ENIGMA exon-level table assigns exon 11 protein-truncating variants to PM5_Strong (PTC).	cspec vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	No de novo framework is used for this BRCA2 VCEP assessment, and no de novo evidence was identified.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 could not be assessed.	cspec
PP2	N/A	PP2 is not used in this BRCA2 VCEP framework.	cspec
PP3	N/A	This variant is a nonsense change rather than a missense, in-frame, silent, or non-canonical intronic variant used for BRCA2 PP3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, below the BRCA2 PP3 protein-impact threshold of 0.30.	spliceai bayesdel cspec
PP4	Met	BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands. This is above the ENIGMA PP4 supporting threshold of 2.08 and below the moderate threshold of 4.3, so PP4_Supporting is met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRCA2 BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA2 BS1 supporting threshold of filter allele frequency greater than 0.002% or strong threshold greater than 0.01%. BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified that this variant was observed in individuals without features of BRCA2-related Fanconi anemia in a manner that could be scored under the BRCA2 BS2 point system. BS2 was not assessed.	cspec
BS3	Not assessed	No variant-specific calibrated functional study showing no damaging effect was identified for c.2818C>T in the ENIGMA BRCA1/2 functional assay table. BS3 was therefore not assessed.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, so BS4 could not be assessed.	cspec
BP1	N/A	This variant is a nonsense change, not a silent, missense, or in-frame variant outside a clinically important domain, so BP1 does not apply.	cspec
BP2	N/A	BP2 is not used in this BRCA2 VCEP framework.	cspec
BP3	N/A	BP3 is not used in this BRCA2 VCEP framework.	cspec
BP4	N/A	This variant is a nonsense change rather than a missense, in-frame, silent, or non-canonical intronic variant used for BRCA2 BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the BP4 rule is not designed for this exonic stop-gain context.	spliceai bayesdel cspec
BP5	Not met	BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands. This is above the benign BP5 supporting threshold of 0.48 and is in the pathogenic rather than benign direction, so BP5 is not met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not used in this BRCA2 VCEP framework.	cspec
BP7	N/A	This variant is a nonsense change, not a silent or qualifying intronic variant for BP7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BP7 is not used for this protein-truncating context.	spliceai cspec

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