Submissions for variant NM_007294.4(BRCA1):c.4524G>A (p.Trp1508Ter)

dbSNP: rs80356885

Total submissions: 29

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, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048586	SCV000076599	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-07	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. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or peritoneal cancer (PMID: 11504767, 20960228, 22006311, 25452441, 25863477, 27082205). This variant is also known as 4643G>A. ClinVar contains an entry for this variant (Variation ID: 55221). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129129	SCV000183847	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4524. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Loman N et al. J. Natl. Cancer Inst., 2001 Aug;93:1215-23; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bu R et al. Int. J. Cancer. 2016 Sep;139:1091-7; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48(2):58-63; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Demir S et al. J BUON;25:1337-1347; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). Of note, this alteration is also designated as 4643G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Pathway Genomics	RCV000077575	SCV000223755	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048586	SCV000271319	pathogenic	Hereditary breast 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	2023-06-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Laitman et al., 2011; Walsh et al., 2011; Bayraktar et al., 2012; Lynce et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4643G>A; This variant is associated with the following publications: (PMID: 26250392, 22009639, 11504767, 24830819, 29506128, 34290354, 34657373, 28888541, 33858029, 25525159, 20960228, 12402332, 22006311, 27082205, 29446198, 30199306, 33087929, 25863477, 29021639, 27208206, 25452441)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236102	SCV000296378	pathogenic	not provided	2021-02-26	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 30199306 (2018), 29506128 (2018), 29446198 (2018), 29021639 (2017), 27082205 (2016), 26250392 (2015), 25863477 (2015)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077575	SCV000325992	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077575	SCV000489091	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048586	SCV000494394	pathogenic	Hereditary breast 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, part of Exact Sciences	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, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129129	SCV000912007	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 30199306, 32862574, 33471991, 34290354, 35464868; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000048586	SCV002025933	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000236102	SCV003809690	pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000048586	SCV004046230	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing	This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer as well as other types of cancer (PMID: PMID: 25863477, 11504767, 25452441, 27082205, 22006311). Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). The c.4587G>A (p.Trp1529Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4587G>A (p.Trp1529Ter) variant is classified as Pathogenic.
Baylor Genetics	RCV000077575	SCV004212734	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000236102	SCV004224838	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	PM2, PM5_strong, PVS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492388	SCV004240268	pathogenic	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077575	SCV004817662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 33471991; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
NHS Central & South Genomic Laboratory Hub	RCV004584141	SCV005068248	pathogenic	Inherited breast cancer and ovarian cancer	2024-07-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077575	SCV000109378	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-11-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077575	SCV000145114	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236102	SCV001550566	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000077575	SCV003927922	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-01	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077575	SCV004243983	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing