Submissions for variant NM_000059.4(BRCA2):c.10234A>G (p.Ile3412Val)

gnomAD frequency: 0.03864  dbSNP: rs1801426

Total submissions: 43

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112853	SCV000245314	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 0.02972 (Asian), 0.126 (African), derived from 1000 genomes (2012-04-30).
Counsyl	RCV000112853	SCV000154054	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
Ambry Genetics	RCV000130982	SCV000185899	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112853	SCV000196032	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120373	SCV000202310	benign	not specified	2015-03-19	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000130982	SCV000267029	benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120373	SCV000301751	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000361728	SCV000383811	benign	Fanconi anemia complementation group D1	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000112853	SCV000383812	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414645	SCV000492484	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000267039	SCV000494298	benign	Hereditary breast ovarian cancer syndrome	2014-01-13	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034426	SCV000511440	benign	not provided	2016-06-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130982	SCV000537369	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120373	SCV000538466	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
Baylor Genetics	RCV000460200	SCV000541023	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000267039	SCV000560423	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477053	SCV000575738	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-17	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120373	SCV000586996	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034426	SCV000602768	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000112853	SCV000743531	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112853	SCV000744797	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769708	SCV000901127	benign	Breast and/or ovarian cancer	2015-07-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120373	SCV001470191	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	RCV000267039	SCV002025890	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000267039	SCV002515173	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000130982	SCV002533200	benign	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120373	SCV002551863	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112853	SCV004016847	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112853	SCV004846283	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034426	SCV000043241	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120373	SCV000084525	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112853	SCV000145770	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-05	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112853	SCV000189292	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-14	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120373	SCV000588020	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353766	SCV000592321	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile3412Val variant has been previously reported in the literature in 59 of 4707 (frequency of 0.006) probands with breast or esophageal cancer and was also identified in 33 of 5486 (frequency of 0.003) controls increasing the likelihood that this is a low frequency benign variant (Capanu_2011_21520273, Vehmanen_1997_ 9150152, Freedman_2004_15317758, Johnson_2007­_17341484, Bergthorsson_2001_11389159, Kuusisto_2011_­21356067, Palmieri_2002_12453858, Hu_2004_14647438). The variant was also identified in the LOVD (4X), UMD (30X), and BIC (111X) databases. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1801426) with a global minor allele frequency (MAF) of 0.043 (1000 genomes), increasing the likelihood that this is a low frequency benign variant. The Ile3412 residue is not highly conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In the UMD database, this variant has been identified in three individuals with a second pathogenic variant with a breast or ovarian cancer phenotype, and also found co-occurring with a deleterious BRCA2 mutation 1493delA in a cell line derived from a primary breast cancer (Teng 1996), thereby increasing the likelihood that this variant does not have clinical significance. In addition, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). In summary, based on the above information, this variant is classified as benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000112853	SCV000733345	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034426	SCV000778729	benign	not provided	2016-12-19	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000130982	SCV000787916	benign	Hereditary cancer-predisposing syndrome	2018-03-02	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120373	SCV001798663	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120373	SCV001905736	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120373	SCV001956884	benign	not specified		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000460200	SCV002520853	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000112853	SCV004243898	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing