Submissions for variant NM_000059.4(BRCA2):c.3869G>A (p.Cys1290Tyr)

gnomAD frequency: 0.00307  dbSNP: rs41293485

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113233	SCV000245029	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01423 (African), derived from 1000 genomes (2012-04-30).
Invitae	RCV000167839	SCV000072307	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113233	SCV000154085	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-03-18	criteria provided, single submitter	literature only
Ambry Genetics	RCV000128895	SCV000172755	benign	Hereditary cancer-predisposing syndrome	2014-07-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Pathway Genomics	RCV000113233	SCV000223761	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113233	SCV000267762	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120338	SCV000332977	benign	not specified	2015-07-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113233	SCV000383689	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-02	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000319921	SCV000383690	likely benign	Fanconi anemia complementation group D1	2018-02-02	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics	RCV000467710	SCV000541061	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000113233	SCV000575737	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120338	SCV000593713	benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514107	SCV000602782	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514107	SCV000610415	likely benign	not provided	2017-06-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128895	SCV000683588	benign	Hereditary cancer-predisposing syndrome	2015-08-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120338	SCV001469680	benign	not specified	2020-06-15	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000514107	SCV002010375	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167839	SCV002026095	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167839	SCV002515268	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000128895	SCV002533829	benign	Hereditary cancer-predisposing syndrome	2020-10-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120338	SCV002550327	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149596	SCV003838154	benign	Breast and/or ovarian cancer	2022-05-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113233	SCV004016854	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113233	SCV000054049	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-01	no assertion criteria provided	clinical testing
ITMI	RCV000120338	SCV000084490	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113233	SCV000146322	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120338	SCV000591880	benign	not specified		no assertion criteria provided	clinical testing	The p.Cys1290Tyr variant has been identified in 15 out of 5374 proband chromosomes (frequency 0.003) in individuals with breast cancer phenotype, however no normal population controls were included in these studies (Dufloth 2005, Borg 2010, Wagner 1999, Fackenthal 2011, Cherbal 2010). However, it is listed in dbSNP database as coming from a "clinical source" (ID#: rs41293485) with a "global minor allele frequency" of 0.003, therefore increasing the likelihood this variant is benign. The p.Cys1290 residue is not conserved in mammals and the variant amino acid tyrosine (Tyr) is present in cat, decreasing the likelihood that this variant has functional significance. In addition, in silico or computational analyses (Polyphen2, AlignGVGD, Sift) do not suggest this variant has an impact on the protein function. In the UMD database, this variant has been identified in 1 (out of 7) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. This variant was identified in the BIC database and indicated as having no clinical significance in 47 entries. In summary, based on the above information, this variant is classified as Benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000514107	SCV000778668	likely benign	not provided	2017-03-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128895	SCV000886673	likely benign	Hereditary cancer-predisposing syndrome	2018-09-06	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120338	SCV001906030	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000514107	SCV001930523	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120338	SCV001956990	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514107	SCV001969109	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514107	SCV002035905	likely benign	not provided		no assertion criteria provided	clinical testing