ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9196C>T (p.Gln3066Ter) (rs80359180)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000235644 SCV000885103 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing The BRCA2 c.9196C>T; p.Gln3066Ter variant (rs80359180), also known as c.9424C>T, has been described in individuals with breast cancer, ovarian cancer, and Fanconi anemia (Alter 2007, Cunningham 2014, Fackenthal 2012, Offit 2003, Song 2014). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 9347) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Alter B et al. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 Feb 7;4:4026. Fackenthal J et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012 Sep 1;131(5):1114-23. Offit K et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst. 2003 Oct 15;95(20):1548-51. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9.
Ambry Genetics RCV000131052 SCV000185982 pathogenic Hereditary cancer-predisposing syndrome 2017-07-31 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) RCV000077463 SCV000147566 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000257912 SCV000219421 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-01 criteria provided, single submitter clinical testing
Color RCV000131052 SCV000684033 pathogenic Hereditary cancer-predisposing syndrome 2016-09-23 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077463 SCV000328076 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077463 SCV000677706 pathogenic Breast-ovarian cancer, familial 2 2015-07-13 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077463 SCV000282469 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 RCV000235644 SCV000292978 pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9196C>T at the cDNA level and p.Gln3066Ter (Q3066X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 9424C>T. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in multiple individuals with breast or ovarian cancer, including at least one male with a personal and family history of breast cancer (Tai 2007, Fackenthal 2012, Cunningham 2014, Couch 2015, Eccles 2016). BRCA2 Gln2066Ter has also been found to co-occur with another BRCA2 pathogenic variant in at least two cases of Fanconi anemia (Offit 2003, Alter 2007). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000257912 SCV000695217 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.9196C>T variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.9235delG). One in-silico tool predicts damaging outcome for this variant. This variant has been reported in multiple Fanconi anemia or HBOC patients and is not found in 121194 control chromosomes. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae RCV000257912 SCV000073758 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 3066 (p.Gln3066*) of 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 reported in individuals with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 24504028, 26845104, 26681682, 24728189, 14559878, 16825431). ClinVar contains an entry for this variant (Variation ID: 9347). 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 RCV000257912 SCV000967781 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-08 criteria provided, single submitter clinical testing The p.Gln3066X variant in BRCA2 has been reported >10 individuals with BRCA2-ass ociated cancers and in 2 individuals with Fanconi anemia have had a second BRCA2 pathogenic variant (Offit 2003, Alter 2007, Tai 2007, Fackenthal 2012, Cunningh am 2014, Song 2014, Couch 2015, Eccles 2016, Breast Cancer Information Core (BIC )). It was also absent from large population studies. This nonsense variant lead s to a premature termination codon at position 3066, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gen e is an established disease mechanism in hereditary breast and ovarian cancer (H BOC). In addition, this variant was classified as Pathogenic by the ClinGen-appr oved ENIGMA expert panel (ClinVar SCV000282469.1). In summary, this variant meet s criteria to be classified as pathogenic for HBOC in an autosomal dominant mann er. ACMG/Amp Criteria Applied: PVS1, PS4, PM2.
OMIM RCV000009941 SCV000030162 pathogenic Fanconi anemia, complementation group D1 2007-01-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077463 SCV000296693 pathogenic Breast-ovarian cancer, familial 2 2015-03-30 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000257912 SCV000587991 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077463 SCV000109261 pathogenic Breast-ovarian cancer, familial 2 2012-10-26 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210196 SCV000266051 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing

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