ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5681dupA (p.Tyr1894Terfs) (rs80359527)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129296 SCV000184057 pathogenic Hereditary cancer-predisposing syndrome 2017-10-10 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) RCV000031569 SCV000146665 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129296 SCV000911073 pathogenic Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031569 SCV000327262 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031569 SCV000488449 pathogenic Breast-ovarian cancer, familial 2 2016-03-31 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031569 SCV000282411 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000482761 SCV000564787 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA2 c.5681dupA at the cDNA level and p.Tyr1894Ter (Y1894X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGTT[dupA]CGAG. 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. This variant, previously reported as BRCA2 5909insA, has been observed in association with hereditary breast and ovarian cancer (Verhoog 1999, Tai 2007, Cao 2016). This variant is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044718 SCV000916895 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5681dupA (p.Tyr1894X) 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. ***). The variant was absent in 245372 control chromosomes. c.5681dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000044718 SCV000072731 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1894*) 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 particular variant has been reported in individuals with breast and/or ovarian cancer (PMID: 11241844, 16683254, 23697973). This variant is also known as 5909insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37988). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044718 SCV000605821 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-12 criteria provided, single submitter clinical testing The p.Tyr1894X variant in BRCA2 has been reported in at least 8 individuals here ditary breast and or ovarian cancer (HBOC; Edwards 2001, Li 2008, Solano 2012, B reast Cancer Information Core (BIC) database) and one individual with unknown cl inical status with a possible history of familial breast and/or ovarian cancer w ho underwent genetic screening for BRCA1 and BRCA2 (van der Hout 2006). It was a lso identified in 1/17242 of East Asian chromosomes by the Genome Aggregation Da tabase (gnomAD; http://gnomad.broadinstitude.org; dbSNP rs80359527); however, th is frequency is low enough to be consistent with the frequency of HBOC in the ge neral population. This nonsense variant is a result of a duplication of one base pair at position 5681, which creates a premature termination codon at amino aci d position 1894. This alteration is then predicted to lead to a truncated or abs ent protein. Heterozygous loss of function of the BRCA2 gene is an established d isease mechanism in hereditary breast and ovarian cancer. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA e xpert panel (SCV000282411.1). In summary, this variant meets criteria to be clas sified as pathogenic for hereditary breast and ovarian cancer in an autosomal do minant manner based upon predicted impact on the protein, presence in multiple a ffected individuals and low frequency in controls.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031569 SCV000296655 pathogenic Breast-ovarian cancer, familial 2 2015-11-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482761 SCV000887856 pathogenic not provided 2015-11-17 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044718 SCV000587790 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031569 SCV000054174 pathogenic Breast-ovarian cancer, familial 2 2011-11-29 no assertion criteria provided clinical testing

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