ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3937C>T (p.Gln1313Ter) (rs80357318)

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Total submissions: 11
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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) RCV000031137 SCV000300046 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048386 SCV000076399 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1313*) in the BRCA1 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 the literature in individuals affected with breast and/or ovarian cancer (PMID: 7837387, 22010008, 25863477, 27153395). ClinVar contains an entry for this variant (Variation ID: 37556). 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 RCV000131882 SCV000186937 pathogenic Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031137 SCV000325795 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482757 SCV000566473 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.3937C>T at the cDNA level and p.Gln1313Ter (Q1313X) at the protein level. 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, also known as BRCA1 4056C>T using alternate nomenclature, has been reported in multiple Hereditary Breast and Ovarian Cancer families and is considered pathogenic (Shattuck-Eidens 1995, Maillet 2006, Caux-Moncoutier 2011, Rummel 2013, Kang 2015).
Color RCV000131882 SCV000683140 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048386 SCV000699085 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-20 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3937C>T (p.Gln1313X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121570 control chromosomes. Multiple publications cite the variant in affected individuals including a very large HBOC that was found to segregate with disease (Miki_1994). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as clinical significance. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002640 SCV001160625 pathogenic not specified 2019-05-28 criteria provided, single submitter clinical testing The BRCA1 c.3937C>T; p.Gln1313Ter variant (rs80357318), also known as 4056C>T, is reported in the literature in multiple individuals and families affected with breast and ovarian cancer (Heramb 2018, Kang 2015, Lee 2011, Maxwell 2016, Miki 1994, Rebbeck 2018, Shattuck-Eidens 1995). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37556), and is absent from general population databases (Exome Variant Server, 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 to be pathogenic. References: Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Lee E et al. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol. 2011 Nov 20;29(33):4373-80. Maxwell KN et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 May 5;98(5):801-817. Miki Y et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66-71. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Shattuck-Eidens D et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995 Feb 15;273(7):535-41.
Sharing Clinical Reports Project (SCRP) RCV000031137 SCV000053736 pathogenic Breast-ovarian cancer, familial 1 2009-10-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031137 SCV000144920 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048386 SCV000587360 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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