ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4965C>G (p.Tyr1655Ter) (rs80358721)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000496311 SCV000602864 pathogenic not specified 2017-02-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000128925 SCV000172795 pathogenic Hereditary cancer-predisposing syndrome 2018-03-29 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000031517 SCV000146514 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000128925 SCV000537670 pathogenic Hereditary cancer-predisposing syndrome 2015-04-10 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031517 SCV000327115 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031517 SCV000487907 pathogenic Breast-ovarian cancer, familial 2 2015-12-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195354 SCV000591934 pathogenic Hereditary breast and ovarian cancer syndrome 2012-12-12 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000496311 SCV000588096 pathogenic not specified 2017-04-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031517 SCV000300809 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Fulgent Genetics,Fulgent Genetics RCV000762918 SCV000893330 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000044533 SCV000210343 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.4965C>G at the cDNA level and p.Tyr1655Ter (Y1655X) at the protein level. The substitution, also known as BRCA2 5193C>G using alternate nomenclature, creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 Tyr1655Ter has been reported in patients with histories consistent with Hereditary Breast and Ovarian Cancer (Ramus 2007, Sakai 2009, Castro 2013, Song 2014) and is considered pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785221 SCV000923789 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000195354 SCV000267859 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195354 SCV000694816 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4965C>G (p.Tyr1655X) 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. p.Arg3128X, p.Glu3111X). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121918 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It was observed in several breast and/or ovarian cancer patients indicating pathogenicity. It has also been reported 21 times in BIC which supports the fact that this variant is a recurrent mutation. Additionally, a functional study demonstrated the variant to impair homology directed repair activity of BRCA2 which is a known to be important for BRCA2s role in tumor suppression. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000195354 SCV000072546 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1655 (p.Tyr1655*). It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80358721, ExAC 0.002%). This variant has been reported in individuals affected with breast, ovarian and prostate cancer (PMID: 20858050, 26681312, 24728189, 21709188, 17688236, 23569316). This variant is also known as 5685C>G and 5193C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37936). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000194794 SCV000223921 pathogenic Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1 2015-02-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000195354 SCV000271328 pathogenic Hereditary breast and ovarian cancer syndrome 2015-03-23 criteria provided, single submitter clinical testing The p.Tyr1655X variant in BRCA2 has been reported in at least 5 individuals with BRCA2-associated cancers (Ramus 2007, Bayraktar 2012, Castro 2013, Chong 2014). This variant has also been identified in 1/65580 European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs80358721). T his nonsense variant leads to a premature termination codon at position 1655, wh ich is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovar ian cancer (HBOC). In summary, this variant meets criteria to be classified as p athogenic for HBOC in an autosomal dominant manner based upon the predicted impa ct to the protein and low frequency in controls.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031517 SCV000267775 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Pathway Genomics RCV000031517 SCV000223757 pathogenic Breast-ovarian cancer, familial 2 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044533 SCV000296707 pathogenic not provided 2015-03-12 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195354 SCV000587734 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031517 SCV000054122 pathogenic Breast-ovarian cancer, familial 2 2013-01-03 no assertion criteria provided clinical testing
True Health Diagnostics RCV000128925 SCV000805244 pathogenic Hereditary cancer-predisposing syndrome 2018-05-30 no assertion criteria provided clinical testing

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