ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.1018C>T (p.Arg340Ter) (rs41293455)

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Total submissions: 32
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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) RCV000019244 SCV000282327 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048523 SCV000076536 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1443*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs41293455, ExAC 0.02%). This variant has been reported in many individuals with hereditary breast and ovarian cancer (PMID: 16030099, 23233716, 19656415, 22798144). It is known to be a common cause of disease in the French Canadian population (PMID: 15883839, 10422801, 20694749, 11250694). This variant is also known as 4446C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 17675). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131880 SCV000186935 pathogenic Hereditary cancer-predisposing syndrome 2017-11-07 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
GeneDx RCV000235131 SCV000210173 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4327C>T at the cDNA level and p.Arg1443Ter (R1443X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as BRCA1 4446C>T using alternate nomenclature, has been observed in multiple families with early-onset breast and ovarian cancer and has been reported as a recurrent variant in the French Canadian and Hispanic populations (Castilla 1994, Simard 2007, Zhang 2011, Weitzel 2013, Cruz-Correa 2017). We consider this variant to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735445 SCV000219242 pathogenic Breast and/or ovarian cancer 2017-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000019244 SCV000220762 pathogenic Breast-ovarian cancer, familial 1 2014-10-02 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000235131 SCV000225648 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000019244 SCV000267710 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235131 SCV000296337 pathogenic not provided 2015-05-08 criteria provided, single submitter clinical testing
GeneKor MSA RCV000239083 SCV000296802 pathogenic not specified 2016-07-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019244 SCV000325921 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000131880 SCV000537634 pathogenic Hereditary cancer-predisposing syndrome 2016-06-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000159989 SCV000540934 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genologica Medica RCV000019244 SCV000577931 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000048523 SCV000588057 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048523 SCV000591505 pathogenic Hereditary breast and ovarian cancer syndrome 2013-06-21 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000019244 SCV000593678 pathogenic Breast-ovarian cancer, familial 1 2016-11-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000235131 SCV000602710 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The BRCA1 c.4327C>T; p.Arg1443Ter variant (rs41293455), also known as 4446C>T for traditional nomenclature, is reported in the literature in multiple individuals with hereditary breast and ovarian cancer syndrome (Castilla 1994, de Jonge 2017, Rashid 2016, Sun 2017, Susswein 2016, Zhang 2011). This variant is also described as a founder variant in the French Canadian population (Cavallone 2010, Neuhausen 2000, Tonin 1999, Vezina 2005). It is reported by multiple laboratories in ClinVar (Variation ID: 17675), and found in the general population with a low overall allele frequency of 0.002% (6/246148 alleles) in the Genome Aggregation Database. 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 to be pathogenic. REFERENCES Castilla LH et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. Cavallone L et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer. 2010 Dec;9(4):507-17. de Jonge MM et al. Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report. Eur J Cancer. 2017 Feb;72:215-225. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2(2):77-81. Rashid MU et al. High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer. 2016 Aug 23;16(1):673. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. 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. Tonin PN et al. Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet. 1999 May;55(5):318-24. Vezina H et al. Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet. 2005 Jul;117(2-3):119-32. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048523 SCV000605740 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-28 criteria provided, single submitter clinical testing The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers (Vezina 2005, Hall 2009). It has also been identi fied in 1/6614 European chromosomes by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs41293455). This nonsense variant leads to a premature termination codon at position 1443, which is predicted to lead to a truncated or absent protein. In addition, functional studies provide some evide nce that this variant results in a truncated protein (Caligo 2009). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in indiv iduals with hereditary breast and ovarian cancer (HBOC). In addition, this varia nt was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282327.1). In summary, this variant meets our crite ria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Fulgent Genetics,Fulgent Genetics RCV000515235 SCV000611253 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048523 SCV000699132 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The c.4327C>T (p.Arg1443X) variant in BRCA1 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.000016 (2/121390 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant has been reported in multiple HBOC families and was shown to segregate with disease phenotype. It has been classified as pathogenic by multiple reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000019244 SCV000743394 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000019244 SCV000744615 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763000 SCV000893445 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000019244 SCV000039532 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019244 SCV000109372 pathogenic Breast-ovarian cancer, familial 1 2013-11-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019244 SCV000145057 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000159989 SCV000280026 pathogenic Familial cancer of breast no assertion criteria provided case-control
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048523 SCV000587391 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000019244 SCV000733611 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000235131 SCV000778740 pathogenic not provided 2016-11-28 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735445 SCV000863581 pathogenic Breast and/or ovarian cancer 2015-12-07 no assertion criteria provided clinical testing

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