ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4731del (p.Glu1577fs) (rs397507740)

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Total submissions: 7
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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) RCV000239279 SCV000783816 pathogenic Breast-ovarian cancer, familial 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000530337 SCV000635400 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1577Aspfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25428789). ClinVar contains an entry for this variant (Variation ID: 252834). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000570296 SCV000668671 pathogenic Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing The c.4731delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4731, causing a translational frameshift with a predicted alternate stop codon (p.E1577Dfs*2). This mutation (referred to as 4959delA) has been previously reported in a 34-year-old African American female diagnosed with triple negative breast cancer, who also had a family history of breast and ovarian cancer (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan; 149(1):31-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000239279 SCV000677825 likely pathogenic Breast-ovarian cancer, familial 2 2017-04-10 criteria provided, single submitter clinical testing
GeneDx RCV000657227 SCV000778953 pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.4731delA at the cDNA level and p.Glu1577AspfsX2 (E1577DfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is TTGA[delA]TTAG. The deletion causes a frameshift which changes a Glutamic Acid to an Aspartic Acid at codon 1577, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4731delA, previously reported as BRCA2 4959delA using alternate nomenclature, as been observed in at least one individual with triple negative breast cancer and a family history of breast and ovarian cancer (Churpek 2015). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000530337 SCV001362126 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4731delA (p.Glu1577AspfsX2) 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. The variant was absent in 251074 control chromosomes (gnomAD). c.4731delA has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Churpek_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000239279 SCV000297437 pathogenic Breast-ovarian cancer, familial 2 2008-08-13 no assertion criteria provided clinical testing

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