ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6755_6756CT[1] (p.Leu2253fs) (rs80359623)

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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) RCV000113638 SCV000301104 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 RCV000045041 SCV000073054 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-09 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 11 of the BRCA2 mRNA (c.6757_6758delCT), causing a frameshift at codon 2253. This creates a premature translational stop signal (p.Leu2253Phefs*7) and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular truncation has been reported in the literature in an individual affected with breast and ovarian cancer (PMID: 11606101). This variant has also been reported as 6985delCT in the literature. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162933 SCV000213420 pathogenic Hereditary cancer-predisposing syndrome 2017-03-15 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 RCV000113638 SCV000327515 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000522313 SCV000617470 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA2 is denoted c.6757_6758delCT at the cDNA level and p.Leu2253PhefsX7 (L2253FfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTCT[delCT]TTTTA. The deletion causes a frameshift which changes a Leucine to a Phenylalanine at codon 2253, and creates a premature stop codon at position 7 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.6757_6758delCT, also denoted 6985delCT using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Schorge 2001, Lubinski 2004, Pritchard 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000522313 SCV000887888 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing
Color RCV000162933 SCV000906927 pathogenic Hereditary cancer-predisposing syndrome 2018-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045041 SCV000918813 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6757_6758delCT (p.Leu2253PhefsX7) 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. p.Arg2318X, p.Gln2342fsX17). The variant was absent in 121130 control chromosomes. c.6757_6758delCT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and prostate cancer (Bosdet_2013, Euhus_2002, Schorge_2001, Lubinski_2004, Pritchard_2016). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113638 SCV000146924 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113638 SCV000297548 pathogenic Breast-ovarian cancer, familial 2 2010-01-13 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045041 SCV000587868 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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