ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4591A>T (p.Lys1531Ter) (rs1555283865)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657707 SCV000779456 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4591A>T at the cDNA level and p.Lys1531Ter (K1531X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Using alternate nomenclature, this variant would be defined as BRCA2 c.4819A>T. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000557526 SCV000694786 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-29 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4591A>T (p.Lys1531X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.7757G>A/p.Trp2586X, c.8575delC/p.Gln2859fsX4). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120446 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000557526 SCV000635387 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1531 (p.Lys1531*) of the BRCA2 gene. It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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