ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4587dup (p.Lys1530fs) (rs745456776)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000238798 SCV000300768 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000195630 SCV000255253 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys1530Glufs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with BRCA2-related disease. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238798 SCV000296652 pathogenic Breast-ovarian cancer, familial 2 2015-07-23 criteria provided, single submitter clinical testing
GeneDx RCV000484375 SCV000568703 pathogenic not provided 2015-11-09 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.4587dupG at the cDNA level and p.Lys1530GlufsX4(K1530EfsX4) at the protein level. The normal sequence, with the base that is duplicated in braces, is GCGG[G]AAAAAAG. The duplication causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 1530, and creates a premature stop codon at position 4 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000195630 SCV000694785 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4587dupG (p.Lys1530Glufs) 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.4965C>G/p.Tyr1655X, c.5073dupA/p.Trp1692fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120446 control chromosomes from ExAC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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