ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1257del (p.Cys419fs) (rs80359272)

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Total submissions: 11
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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) RCV000031314 SCV000300412 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000043768 SCV000071781 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys419Trpfs*11) 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 individuals affected with breast and/or ovarian cancer (PMID: 15131399, 22762150, 25682074). This variant is also known as 1485delT in the literature. ClinVar contains an entry for this variant (Variation ID: 37733). 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 RCV000130282 SCV000185127 pathogenic Hereditary cancer-predisposing syndrome 2018-05-09 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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031314 SCV000326527 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000480855 SCV000568453 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.1257delT at the cDNA level and p.Cys419TrpfsX11 (C419WfsX11) at the protein level. The normal sequence, with the base that is deleted in brackets, is CATG[delT]GACC. The deletion causes a frameshift which changes a Cysteine to a Tryptophan at codon 419, and creates a premature stop codon at position 11 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.1257delT, also published as BRCA2 1485delT using alternate nomenclature, has been observed in individuals with breast cancer (Wong-Brown 2015). We consider this variant to be pathogenic.
Color RCV000130282 SCV000683409 pathogenic Hereditary cancer-predisposing syndrome 2017-04-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000043768 SCV000694526 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-30 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1257delT (p.Cys419Trpfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If the mutant protein survives NMD, it is predicted to truncate OB1, OB2, and OB3 domains whch take part in ssDNA binding. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1265delA, c.1842dupT, c.2400_2401delTA, etc. ). This variant is absent in 120556 control chromosomes from ExAC. This variant has been reported in one TNBC patient in literature and three affected individuals in BIC. It has also been reported in multiple individuals undergoing BRCA1/2 testing by clinical labs and databases. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000031314 SCV000785374 pathogenic Breast-ovarian cancer, familial 2 2017-07-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031314 SCV000053919 pathogenic Breast-ovarian cancer, familial 2 2009-02-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031314 SCV000145841 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043768 SCV000587587 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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