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

Total submissions: 20

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.