ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4524G>A (p.Trp1508Ter) (rs80356885)

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Total submissions: 18
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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) RCV000077575 SCV000300134 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 RCV000048586 SCV000076599 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1508*) 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 an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228), individuals with breast cancer (PMID: 25863477, 11504767, 25452441, 27082205), and an individual with peritoneal cancer (PMID: 22006311). This variant is also known as 4643G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55221). 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 RCV000129129 SCV000183847 pathogenic Hereditary cancer-predisposing syndrome 2018-01-02 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)
Pathway Genomics RCV000077575 SCV000223755 pathogenic Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000048586 SCV000271319 pathogenic Hereditary breast and ovarian cancer syndrome 2015-07-14 criteria provided, single submitter clinical testing The p.Trp1529X variant in BRCA1 has been reported in 1 individual (reported as p .Tyr1508X predicted from NM_007294.3) whose clinical status is either affected w ith a BRCA1-associated cancer or was asymptomatic but from a high risk breast/ov arian cancer family (Laitman 2011). This variant has not been identified in lar ge population studies. This nonsense variant leads to a premature termination co don at position 1529, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of BRCA1 function is an established disease mechanism in BR CA1-associated cancers. In summary, this variant meets our criteria to be classi fied as pathogenic for BRCA1-associated cancers in an autosomal dominant manner based upon the predicted impact to the protein.
GeneDx RCV000236102 SCV000292523 pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4524G>A at the cDNA level and p.Trp1508Ter (W1508X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also published as 4643G>A, has been observed in association with Hereditary Breast and Ovarian Cancer syndrome and is considered pathogenic (Laitman 2011, Walsh 2011, Bayraktar 2012, Lynce 2015).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236102 SCV000296378 pathogenic not provided 2015-08-31 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077575 SCV000325992 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077575 SCV000489091 pathogenic Breast-ovarian cancer, familial 1 2016-08-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048586 SCV000494394 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4524G>A (p.Trp1508X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.Glu1535X, p.Tyr1563X). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous HBOC patients and is absent in 121246 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneKor MSA RCV000236102 SCV000693539 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000236102 SCV000806952 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762998 SCV000893443 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
Color RCV000129129 SCV000912007 pathogenic Hereditary cancer-predisposing syndrome 2018-02-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001033 SCV001158145 pathogenic not specified 2019-01-16 criteria provided, single submitter clinical testing The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu 2016, Couch 2015, Kang 2015, Laitman 2011, Loman 2001, Lynce 2015,) or other cancer types (Lowery 2018, Rebbeck 2018, Walsh 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 55221), 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: Bu R et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int J Cancer. 2016 Sep 1;139(5):1091-7. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. 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. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Lynce F et al. Deleterious BRCA1/2 mutations in an urban population of Black women. Breast Cancer Res Treat. 2015 Aug;153(1):201-9. 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. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7.
Sharing Clinical Reports Project (SCRP) RCV000077575 SCV000109378 pathogenic Breast-ovarian cancer, familial 1 2010-11-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077575 SCV000145114 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 RCV000048586 SCV000587406 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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