ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2830A>T (p.Lys944Ter) (rs80358533)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077287 SCV000300563 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000131101 SCV000186031 pathogenic Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing The p.K944* pathogenic mutation (also known as c.2830A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 2830. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been detected in multiple high-risk breast and ovarian cancer families to date (Hakansson S et al. Am. J. Hum. Genet. 1997 May;60:1068-78; Jonsson G et al. Cancer Res. 2005 Sep;65:7612-21; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Blay P et al. BMC Cancer. 2013 May;13:243; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Heidemann S et al. Breast Cancer Res. Treat. 2012 Aug;134:1229-39; Vietri MT et al. Clin. Chem. Lab. Med. 2013 Dec;51:2319-24; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J. Med. Genet., 2018 Feb;55:97-103). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000212222 SCV000210293 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2830A>T at the cDNA level and p.Lys944Ter (K944X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA) and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA2 3058A>T by alternate nomenclature, has been reported in multiple individuals with personal and/or family history of breast, ovarian, and/or pancreatic cancer (Hakansson 1997, Peto 1999, Capalbo 2006, Thomassen 2008, Borg 2010, Blay 2013, Lucas 2014). Additionally, Ruud et al. (2001) reported a patient with Fanconi anemia who passed away following a diagnosis of medulloblastoma and resultant chemotherapy toxicity. Follow-up studies on archived tissue by Bodd et al. (2010) revealed compound heterozygosity for BRCA2 Lys944Ter, present in her mother who had a family history of breast and ovarian cancer, and a BRCA2 missense variant, present in her father. We consider this variant to be pathogenic.
Color Health, Inc RCV000131101 SCV000292148 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212222 SCV000296716 pathogenic not provided 2019-11-26 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077287 SCV000326771 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000044070 SCV000540994 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000077287 SCV000605671 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Counsyl RCV000077287 SCV000677672 pathogenic Breast-ovarian cancer, familial 2 2015-08-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496649 SCV000694634 pathogenic Hereditary breast and ovarian cancer syndrome 2021-01-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2830A>T (p.Lys944X) 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. The variant allele was found at a frequency of 8e-06 in 250612 control chromosomes. c.2830A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077287 SCV000744431 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000496649 SCV000838779 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000212222 SCV001450006 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077287 SCV000109084 pathogenic Breast-ovarian cancer, familial 2 2006-11-27 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077287 SCV000146122 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496649 SCV000587645 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077287 SCV000733241 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785217 SCV000923785 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV001028039 SCV001190805 pathogenic Fanconi anemia, complementation group D1 2020-02-05 no assertion criteria provided clinical testing
New York Genome Center RCV000077287 SCV001431059 pathogenic Breast-ovarian cancer, familial 2 2020-03-10 no assertion criteria provided clinical testing The c.2830A>T (p.Lys944Ter) variant identified in the BRCA2 gene of this individual leads to the premature termination of the protein at amino acid 944/3419 (coding exon 11/27). This variant is found with low frequency in gnomAD (3 heterozygotes, 0 homozygotes, allele frequency: 1.06e-5) suggesting it is not a common benign variant in the populations represented in these databases. This variant is reported as Pathogenic in ClinVar (VarID:51355) after review by the Expert Panel and has been reported in many affected individuals in the literature [PMID: 24737347; PMID: 23683081; PMID: 20104584; PMID: 28346442]. It is reported here as Pathogenic.

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