ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3199del (p.Thr1067fs) (rs80359377)

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Total submissions: 9
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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) RCV000077296 SCV000300602 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 RCV000044145 SCV000072158 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr1067Leufs*10) 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 the literature in individuals with a personal and/or family history of hereditary breast and ovarian cancer as well as colorectal cancer (PMID: 15146557, 24156927, 25452441, 28135145). In the literature, this variant is also known as 3427delA. ClinVar contains an entry for this variant (Variation ID: 51421). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077296 SCV000326834 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000483265 SCV000565992 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.3199delA at the cDNA level and p.Thr1067LeufsX10 (T1067LfsX10) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 3427delA. The normal sequence, with the base that is deleted in brackets, is TAAT[delA]CTGT. The deletion causes a frameshift, which changes a Threonine to a Leucine at codon 1067, and creates a premature stop codon at position 10 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.3199delA has been observed in multiple families with hereditary breast and/or ovarian cancer (Gorski 2004, Lubinski 2004, Tea 2014, Couch 2015, Meisel 2017), as well as one individual with ampullary cancer (Villalona-Calero 2016). We consider this variant to be pathogenic.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000577990 SCV000679712 pathogenic Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044145 SCV000918839 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3199delA (p.Thr1067LeufsX10) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.3226_3230delGTAGT, p.Val1076fsX3; c.3264dupT, p.Gln1089fsX10; c.3362C>G, p.Ser1121X). The variant has been reported in multiple families with hereditary breast and/or ovarian cancer (Gorski 2004, Lubinski 2004, Tea 2014, Couch 2015). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 119892 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077296 SCV000109093 pathogenic Breast-ovarian cancer, familial 2 2011-01-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077296 SCV000146188 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 RCV000044145 SCV000587664 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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