ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2253_2254del (p.Asp752fs) (rs398122744)

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Total submissions: 4
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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) RCV000077681 SCV000300501 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000481582 SCV000569421 pathogenic not provided 2016-10-07 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in BRCA2 is denoted c.2253_2254delTG at the cDNA level and p.Asp752LeufsX10 (D752LfsX10) at the protein level. The normal sequence, with the bases that are deleted in braces, is ATAC[TG]ACTT. Using alternate nomenclature, this variant would be defined as BRCA2 2481delTG. The deletion causes a frameshift which changes an Aspartic Acid to a Leucine at codon 752, and creates a premature stop codon at position 10 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 RCV000781073 SCV000918882 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2253_2254delTG (p.Asp752LeufsX10) 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.2287delC, p.His763fsX9; c.2330dupA, p.Asp777fsX11; c.2368G>T, p.Glu790X). The variant was absent in 277038 control chromosomes. To our knowledge, no occurrence of c.2253_2254delTG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
Sharing Clinical Reports Project (SCRP) RCV000077681 SCV000109484 pathogenic Breast-ovarian cancer, familial 2 2011-09-23 no assertion criteria provided clinical testing

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