ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4964dup (p.Tyr1655Ter) (rs398122789)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218684 SCV000273734 pathogenic Hereditary cancer-predisposing syndrome 2018-04-13 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),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077738 SCV000327113 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) RCV000077738 SCV000300807 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 RCV000480916 SCV000568470 pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA2 c.4964dupA at the cDNA level and p.Tyr1655Ter (Y1655X) at the protein level. The normal sequence, with the base that is duplicated in braces, is TGTT[A]CACA. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4964dupA, also denoted BRCA2 5192dupA using alternate nomenclature, has been reported in association with hereditary breast /ovarian cancer (Peixoto 2014). This variant is considered pathogenic.
Invitae RCV000557404 SCV000635415 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1655*) 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 observed in individuals affected with hereditary breast/ovarian cancer (PMID: 24916970). A different variant (c.4965C>G) giving rise to the same protein effect observed here (p.Tyr1655*) has also been seen in many individuals affected with breast, ovarian, and/or prostate cancer (PMID: 20858050, 26681312, 24728189, 21709188, 17688236, 23569316). ClinVar contains an entry for this variant (Variation ID: 91830). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077738 SCV000296733 pathogenic Breast-ovarian cancer, familial 2 2015-02-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077738 SCV000109541 pathogenic Breast-ovarian cancer, familial 2 2009-12-01 no assertion criteria provided clinical testing

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