ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6762del (p.Phe2254fs) (rs80359624)

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Total submissions: 3
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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) RCV000661779 SCV000784095 pathogenic Breast-ovarian cancer, familial 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000236668 SCV000292974 pathogenic not provided 2015-07-07 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.6762delT at the cDNA level. The normal sequence, with the base that is deleted in braces, is CTTTT[T]ACAT. This variant has not, to our knowledge, been reported in the literature. Of note, BRCA2 c.6762delT is known to be in cis with the pathogenic BRCA2 variant, c.6816_6841+1534del1560. The BRCA2 c.6762delT deletion would be expected to cause a frameshift leading to a premature stop codon. However, the large deletion c.6816_6841+1534del1560 occurs prior to the location of the premature stop codon. Thus, BRCA2 c.6762delT is not expected to be clinically significant in this individual or family.,
Integrated Genetics/Laboratory Corporation of America RCV000779977 SCV000916953 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6762delT (p.Phe2254LeufsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.6944_6947delTAAA, p.Ile2315fsX12; c.6952C>T, p.Arg2318X; c.6997_6998delGT, p.Val2333fsX6). The variant was absent in 121018 control chromosomes. To our knowledge, no occurrence of c.6762delT in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. This lab has reported the variant to be in cis with the pathogenic BRCA2 variant c.6816_6841+1534del1560, a large deletion which occurs prior to the location of the current variant of interest, indicating the BRCA2 c.6762delT possibly is not expected to be clinically significant in the individual or family reported by this lab. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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