ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1265del (p.Asn422fs) (rs80359273)

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Total submissions: 13
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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) RCV000031316 SCV000300414 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 RCV000043770 SCV000071783 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the BRCA2 mRNA (c.1265delA), causing a frameshift at codon 422. This creates a premature translational stop signal (p.Asn422Ilefs*8) 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 the literature in individuals affected with ovarian cancer and prostate cancer (PMID: 17148771, 21324516, 21952622, 23569316, 24728189). ClinVar contains an entry for this variant (Variation ID: 37735). This variant is also known as 1493delA in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074512 SCV000108597 pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.1265delA at the cDNA level and p.Asn422IlefsX8 (N422IfsX8) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAA[delA]TATT. The deletion causes a frameshift, which changes an Asparagine to an Isoleucine at codon 422, and creates a premature stop codon at position 8 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.1265delA, previously reported as BRCA2 1493delA, has been reported in several women with ovarian cancer as well as a man with a personal history of prostate cancer and family history of breast, ovarian, and prostate cancers (Risch 2006, Kote-Jarai 2011, Zhang 2011, Song 2014). We consider this variant to be pathogenic.
Ambry Genetics RCV000132260 SCV000187343 pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000132260 SCV000292130 pathogenic Hereditary cancer-predisposing syndrome 2016-03-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074512 SCV000296754 pathogenic not provided 2016-01-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031316 SCV000326529 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000043770 SCV000591733 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000043770 SCV000694527 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1265delA (p.Asn422Ilefs) 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.1310_1313delAAGA, p.Lys437fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/123586 control chromosomes at a frequency of 0.0000162, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in multiple affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000074512 SCV000885117 pathogenic not provided 2017-10-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031316 SCV000053921 pathogenic Breast-ovarian cancer, familial 2 2012-03-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031316 SCV000145843 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 RCV000043770 SCV000587589 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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