ClinVar Miner

Submissions for variant NM_007294.4(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 2019-11-18 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 observed 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 2019-01-16 criteria provided, single submitter clinical testing 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 2019-08-07 criteria provided, single submitter clinical testing The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1508, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55221). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
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 2020-07-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4524G>A (p.Trp1508X) 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 was absent in 251348 control chromosomes. c.4524G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Loman_2001, Phelan_2002, Judkins_2005, Laitman_2011, Walsh_2011, Bayraktar_2012, Bu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve 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.
GeneKor MSA RCV000236102 SCV000693539 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results in a truncated non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant is also known as c.4643G>A in the literature. This particular truncation has been reported in the literature in an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228) in individuals with breast cancer (PMID: 25863477, 11504767) and in an individual with peritoneal cancer (PMID: 22006311). The mutation database ClinVar contains entries for this variant (Variation ID: 55221).
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 2020-01-15 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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