Submissions for variant NM_000059.4(BRCA2):c.9902del (p.Pro3301fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003531265	SCV004323501	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 18593900, 18607349). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant disrupts a stretch of 36 conserved residues (amino acids Ala3270-Gly3305) in BRCA2 which are critical for RAD51-mediated DNA repair activity of the BRCA2 protein (PMID: 17515903, 24323938). While functional studies have not been performed to directly test the effect of this variant on BRCA2 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro3301Glnfs*12) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 118 amino acid(s) of the BRCA2 protein.