ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1832C>A (p.Ser611Ter) (rs80358474)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212216 SCV000883478 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing The BRCA2 c.1832C>A; p.Ser611Ter variant (rs80358474), also known as 2060C>A, has previously been associated with hereditary breast and ovarian cancer syndrome (Kwong 2016, Lubinski 2004, Susswein 2016). This variant is reported multiple times in the ClinVar database as pathogenic (Variation ID: 37764), and is observed in general population databases at a low frequency of 0.001 percent (3/236032 alleles, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Ser611Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/37764/ Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
Ambry Genetics RCV000131056 SCV000185986 pathogenic Hereditary cancer-predisposing syndrome 2017-04-05 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031345 SCV000145963 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131056 SCV000683455 pathogenic Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031345 SCV000326621 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000043906 SCV000591775 pathogenic Hereditary breast and ovarian cancer syndrome 2014-10-24 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031345 SCV000300468 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 RCV000212216 SCV000210278 pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.1832C>A at the cDNA level and p.Ser611Ter (S611X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.1832C>A, previously reported as 2060C>A using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Lubinski 2004, Zhang 2012). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000043906 SCV000694574 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1832C>A (p.Ser611X) 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.1842dupT (p.Asn615X) and c.1855C>T (p.Gln619X). The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals. In addition, multiple reputable databases/clinical laboratories classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000043906 SCV000071919 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser611*) 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 reported in families and individuals with breast and/or ovarian cancer (PMID: 15131399, 26187060, 26681312, 24156927, 26848529). This variant is also known as 2060C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37764). 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 RCV000212216 SCV000296543 pathogenic not provided 2016-04-08 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043906 SCV000587617 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031345 SCV000053950 pathogenic Breast-ovarian cancer, familial 2 2011-12-22 no assertion criteria provided clinical testing

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