ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2808del (p.Lys936fs) (rs398122753)

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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) RCV000077695 SCV000300559 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000129297 SCV000184058 pathogenic Hereditary cancer-predisposing syndrome 2017-12-12 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)
Invitae RCV000204896 SCV000259252 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-31 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide in exon 11 of the BRCA2 mRNA (c.2808delA), causing a frameshift at codon 936. This creates a premature translational stop signal (p.Lys936Asnfs*24) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in individuals affected with breast cancer (PMID: 25428789, 26296701). This variant is also known as 3036delA in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000218847 SCV000279347 pathogenic not provided 2018-03-27 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.2808delA at the cDNA level and p.Lys936AsnfsX24 (K936NfsX24) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATAA[delA]CAAG. The deletion causes a frameshift, which changes a Lysine to an Asparagine at codon 936, and creates a premature stop codon at position 24 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.2808delA, previously reported as 3036delA using alternate nomenclature, has been observed in an individual with male breast cancer, and several women with breast cancer, one of whom was noted to have triple negative disease and a family history of breast cancer (Malone 2006, Churpek 2015, Ellingson 2015, Tung 2015, Guo 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218847 SCV000600525 pathogenic not provided 2017-03-18 criteria provided, single submitter clinical testing
Counsyl RCV000077695 SCV000677756 pathogenic Breast-ovarian cancer, familial 2 2016-12-27 criteria provided, single submitter clinical testing
Color RCV000129297 SCV000683502 pathogenic Hereditary cancer-predisposing syndrome 2015-06-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000204896 SCV000918844 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2808delA (p.Lys936AsnfsX24) 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 (e.g. c.2830A>T (p.Lys944X), c.2833_2834insTT (p.Lys945fsX16), c.2836_2837delGA (p.Asp946fsX12)), in addition, another frameshift variant affecting the same nucleotide position (c.2808_2811delACAA (p.Ala938fsX21) is a common pathogenic variant. The variant allele was found at a frequency of 3.1e-05 in 31890 control chromosomes (in gnomAD and publication data). c.2808delA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Malone 2006, Tung 2015, Churpek 2015, Ellingson 2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077695 SCV000109498 pathogenic Breast-ovarian cancer, familial 2 2011-06-16 no assertion criteria provided clinical testing

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