ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5201_5205delinsGAAAAG (p.Glu1734fs) (rs483353082)

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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) RCV000661398 SCV000783672 pathogenic Breast-ovarian cancer, familial 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507387 SCV000600633 pathogenic not provided 2017-02-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781038 SCV000918810 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5201_5205delinsGAAAAG (p.Glu1734GlyfsX9) 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.5213_5216delCTTA, p.Thr1738fsX2; c.5217_5223delTTTAAGT, p.Tyr1739X; c.5238dupT, p.Asn1747X). The variant was absent in 273414 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5201_5205delinsGAAAAG 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. Based on the evidence outlined above, the variant was classified as likely pathogenic.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000781038 SCV001737427 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-06-04 criteria provided, single submitter clinical testing The BRCA2 c.5201_5205delinsGAAAAG (p.Glu1734Glyfs*9) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). It is also absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals affected with hereditary breast and ovarian cancer or Fanconi anemia. However, truncating variants downstream of the p.Glu1734fs change have been reported in individuals with breast and/or ovarian cancer and are known to be pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1, PM2_Supporting.

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