ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1733del (p.Gly578fs) (rs879255326)

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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) RCV000661865 SCV000784191 pathogenic Breast-ovarian cancer, familial 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneKor MSA RCV000239261 SCV000296814 pathogenic Familial cancer of breast 2017-11-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509861 SCV000607881 pathogenic Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000657341 SCV000779073 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.1733delG at the cDNA level and p.Gly578ValfsX2 (G578VfsX2) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 1961delG. The normal sequence, with the base that is deleted in brackets, is GCAG[delG]TTTA. The deletion causes a frameshift which changes a Glycine to a Valine at codon 578, and creates a premature stop codon at position 2 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 RCV000781160 SCV000919034 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-10 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA2 c.1733delG (p.Gly578ValfsX2) 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.1736T>G (p.Leu579X), c.1796_1800delCTTAT (p.Ser599X), c.2254_2257delGACT (p.Asp752fsX19)). The variant was absent in 245778 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1733delG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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