Submissions for variant NM_007294.4(BRCA1):c.4535G>T (p.Ser1512Ile)

gnomAD frequency: 0.00240  dbSNP: rs1800744

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112356	SCV000244362	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000000000309
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048591	SCV000076604	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000112356	SCV000154028	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-03-19	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112356	SCV000195930	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162492	SCV000212874	benign	Hereditary cancer-predisposing syndrome	2014-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000120258	SCV000226128	benign	not specified	2014-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048591	SCV000494296	benign	Hereditary breast ovarian cancer syndrome	2014-01-24	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120258	SCV000586900	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120258	SCV000593659	benign	not specified	2016-12-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034752	SCV000602672	benign	not provided	2023-09-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162492	SCV000683192	likely benign	Hereditary cancer-predisposing syndrome	2014-11-11	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000112356	SCV000743392	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112356	SCV000744613	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120258	SCV000806953	benign	not specified	2016-11-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000112356	SCV001140518	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112356	SCV001280758	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-08-07	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120258	SCV001469392	benign	not specified	2020-06-15	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000048591	SCV002025932	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034752	SCV002498278	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA1: BS2
Genetics Program, Instituto Nacional de Cancer	RCV000048591	SCV002515214	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162492	SCV002537758	benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120258	SCV002550974	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490467	SCV002803547	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-12-23	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112356	SCV004016787	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112356	SCV004817658	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034752	SCV005251036	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034752	SCV000043157	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120258	SCV000084410	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112356	SCV000145117	benign	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-21	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000112356	SCV000187728	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-24	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000112356	SCV000189343	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-08	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120258	SCV000587407	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120258	SCV000591526	benign	not specified		no assertion criteria provided	clinical testing	The BRCA1, c.4535G>T, p.Ser1512Ile variant has been reported in the literature in 6/2156 proband chromosomes of individuals with HBOC and sporadic breast/ ovarian cancer. It was also identified in 6/1360 of the control chromosomes evaluated (Al-Mulla_2008, Bergthorsson_2001, Young_2009, Wagner_1998, Tavtigian_2006, Phelan_2005, Sanz_2010). The variant has also been previously identified in our laboratory in 6 individuals, and was classified as benign. The variant is reported in the BIC (x58), Exome Server and BOCs databases. It is also listed in the dbSNP database as coming from a "clinical source" (ID#: rs1800744) with a MAF score of 0.001 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. The residue is not conserved in mammals, and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not very predictive of pathogenicity. Functional studies examining the effect of the variant on transcriptional activation found that the variant levels were equal to or higher than that of wild type BRCA1, suggesting that it does not represent a high risk variant & is likely to have low clinical significance (Phelan_2005). Studies have also reported that p.Ser1512Ile has been found to co-occur with other known BRCA1 pathogenic variants numerous times, increasing the likelihood that this variant does not have clinical significance (Bergthorsson_2001, Tavtigian_2006, Phelan_2005). In summary, based on the above information, this variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000112356	SCV000733609	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034752	SCV000778738	benign	not provided	2016-12-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162492	SCV000805231	likely benign	Hereditary cancer-predisposing syndrome	2018-04-25	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120258	SCV001906427	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120258	SCV001953385	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000048591	SCV001977041	benign	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120258	SCV002035335	benign	not specified		no assertion criteria provided	clinical testing