ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9706A>T (p.Lys3236Ter)

dbSNP: rs80359239
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000706708 SCV000835775 pathogenic Hereditary breast ovarian cancer syndrome 2024-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys3236*) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the BRCA2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal and family history of breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 582595). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV003141708 SCV003806624 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-01-11 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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