Submissions for variant NM_007294.4(BRCA1):c.470_471del (p.Leu156_Ser157insTer)

dbSNP: rs80357887

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031189	SCV000282333	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203622	SCV000076650	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser157*) 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 and ovarian cancer (PMID: 11149413, 22970155, 23683081, 24916970). This variant is also known as 589delCT. ClinVar contains an entry for this variant (Variation ID: 37608). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131836	SCV000186891	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The c.470_471delCT pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 470 to 471, causing a translational frameshift with a predicted alternate stop codon (p.S157*). This alteration has been identified as a recurrent mutation in both Spanish and Southern Chinese breast and/or ovarian cancer cohorts (de la Hoya M et al. Int. J. Cancer 2001 Jan;91:137-40; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Kwong A et al. PLoS ONE 2012 Sep;7:e43994). This mutation has also been reported in multiple international HBOC cohorts (Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Fernandes GC et al. Oncotarget 2016 Oct;7(49):80465-80481; Bhaskaran SP et al. Int. J. Cancer 2019 Jan; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Palmero EI et al. Sci Rep. 2018 Jun;8:9188; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Li JY et al. Int. J. Cancer 2019 01;144:281-289; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 589_590delCT in published literature. 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.
GeneDx	RCV000048637	SCV000210001	pathogenic	not provided	2021-11-22	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 (Tang 1999, de la Hoya 2001, Kwong 2012, Blay 2013, Peixoto 2015); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 589_590delCT; This variant is associated with the following publications: (PMID: 17603881, 24249303, 11149413, 22970155, 26187060, 24916970, 28127413, 24578176, 27157322, 12955716, 23199084, 23683081, 18627636, 10340909, 27553291, 28961279, 11802208, 29752822, 28993434, 30702160, 27741520, 29176636, 31825140, 30787465, 32101877)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031189	SCV000326035	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131836	SCV000688515	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 589delCT and 589_590delCT in the literature. 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 detected in over 10 individuals affected with breast and ovarian cancer (PMID: 11802208, 12955716, 16998791, 20617377, 22970155, 27553368, 27741520, 29752822) and in suspected hereditary breast and ovarian cancer families (PMID: 23683081, 24249303, 24916970). 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.
Mendelics	RCV000203622	SCV000839303	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048637	SCV000888925	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with suspected hereditary breast/ovarian cancer syndrome in the published literature (PMIDs: 30702160 (2019), 29907814 (2018), 29752822 (2018), 29446198 (2018), 29176636 (2018), 24916970 (2015), 23683081 (2013), 22970155 (2012), 22762150 (2012), 18627636 (2008), 11149413 (2001), and 10340909 (1999)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203622	SCV001432093	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.470_471delCT (p.Ser157X) 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 251450 control chromosomes. c.470_471delCT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (delaHoya_2002, Judkins_2005, Kwong_2012, Peixoto_2014). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV000031189	SCV002498795	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-10	criteria provided, single submitter	clinical testing	The c.470_471del;p.(Ser157*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37608; PMID: 11149413; PMID: 22970155; PMID: 23683081; PMID: 29907814) - PS4. This variant is not present in population databases (rs80357887- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic
Genetics Program, Instituto Nacional de Cancer	RCV000203622	SCV002515110	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV002496476	SCV002806981	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-05-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000048637	SCV003800425	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	The BRCA1 c.470_471delCT; p.Ser157Ter variant (rs80357887), also known as 589delCT, is reported in several individuals and families with hereditary breast and/or ovarian cancer (de la Hoya 2001, de lay Hoya 2002, Fernandes 2016, Wen 2018). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37608) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes two nucleotides, leading to an immediate nonsense codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: de la Hoya M et al. Spanish family study on hereditary breast and/or ovarian cancer: analysis of the BRCA1 gene. Int J Cancer. 2001 Jan 1;91(1):137-40. PMID: 11149413. de la Hoya M et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002 Feb 1;97(4):466-71. PMID: 11802208. Fernandes GC et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget. 2016 Dec 6;7(49):80465-80481. PMID: 27741520. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. PMID: 28993434.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031189	SCV003807568	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PP1 moderated
Baylor Genetics	RCV000031189	SCV004216965	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-17	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031189	SCV000053789	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-08-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031189	SCV000145594	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000203622	SCV000587056	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Center for Precision Medicine, Meizhou People's Hospital	RCV002250477	SCV002520913	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031189	SCV002589072	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031189	SCV005061351	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control
PreventionGenetics, part of Exact Sciences	RCV004758613	SCV005365604	pathogenic	BRCA1-related disorder	2024-06-01	no assertion criteria provided	clinical testing	The BRCA1 c.470_471delCT variant is predicted to result in premature protein termination (p.Ser157*). This variant, also referred to in the literature as c.589delCT, has been reported in several individuals and families with hereditary breast and/or ovarian cancer (de la Hoya et al. 2001. PubMed ID: 11149413; de la Hoya et al. 2002. PubMed ID: 11802208; Kwong et al. 2012. PubMed ID: 22970155; Peixoto et al. 2014. PubMed ID: 24916970). This variant has not been reported in a large population database, indicating this variant is rare, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37608/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.