ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4276dupA (p.Thr1426Asnfs) (rs80359438)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130745 SCV000185636 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031472 SCV000146399 pathogenic Breast-ovarian cancer, familial 2 2000-08-16 no assertion criteria provided clinical testing
Color RCV000130745 SCV000683609 pathogenic Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031472 SCV000327005 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031472 SCV000300731 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000657226 SCV000778952 pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.4276dupA at the cDNA level and p.Thr1426AsnfsX12 (T1426NfsX12) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGAT[dupA]CATT. The duplication causes a frameshift which changes a Threonine to an Asparagine at codon 1426, and creates a premature stop codon at position 12 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.4276dupA, also defined as BRCA2 4504insA using alternate nomenclature, has been observed in association with hereditary breast and ovarian cancer (Lubinski 2004). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000496461 SCV000918958 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4276dupA (p.Thr1426AsnfsX12) 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. c.4284dupT (p.Gln1429fsX9), c.4398_4402delACATT (p.Leu1466fsX2), and c.4415_4418delAGAA (p.Lys1472fsX6)). The variant was absent in 240852 control chromosomes (gnomAD). The variant, c.4276dupA, has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Lubiniski_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496461 SCV000587707 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031472 SCV000054077 pathogenic Breast-ovarian cancer, familial 2 2008-07-14 no assertion criteria provided clinical testing

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