Submissions for variant NM_000059.4(BRCA2):c.978C>A (p.Ser326Arg)

gnomAD frequency: 0.00082  dbSNP: rs28897706

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077475	SCV000244497	benign	Breast-ovarian cancer, familial, susceptibility to, 2	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 = 0.000583
Invitae	RCV000045896	SCV000073909	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148427	SCV000190126	likely benign	Breast neoplasm	2014-06-01	criteria provided, single submitter	research
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077475	SCV000195956	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162581	SCV000212997	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: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768586	SCV000219297	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000077475	SCV000220357	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-29	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000077475	SCV000383624	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-04-18	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	RCV000354967	SCV000383625	likely benign	Fanconi anemia complementation group D1	2019-04-18	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000444014	SCV000511127	uncertain significance	not provided	2016-07-29	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120308	SCV000538481	uncertain significance	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: Multiple publications classify as VUS/not pathogenic; ExAC: 0.1% (83/72816) of European chromosomes (Finnish and Non-Finnish)
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120308	SCV000586921	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162581	SCV000684091	likely benign	Hereditary cancer-predisposing syndrome	2015-01-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077475	SCV000743254	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	RCV000077475	SCV000744399	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000444014	SCV000805802	likely benign	not provided	2017-07-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000444014	SCV000885104	benign	not provided	2023-02-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000077475	SCV001138985	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262844	SCV001440867	likely benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000444014	SCV002010284	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162581	SCV002532063	benign	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000444014	SCV002545107	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS1:Supporting
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120308	SCV002550269	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ITMI	RCV000120308	SCV000084460	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077475	SCV000109273	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077475	SCV000145798	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	RCV000120308	SCV000591723	benign	not specified		no assertion criteria provided	clinical testing	The c.978C>A, p.Ser326Arg variant has been previously identified in our laboratory in 4 patients with breast cancer as well as pancreatic cancer. It has also been reported in the literature in 11 of 11054 proband chromosomes in individuals with breast, ovarian and prostate cancer patients. The variant was not observed in any of the 206 control chromosomes tested (Edwards_2003, Spearman_2008, Caux-Moncoutier_2010, Sinilnikova_1999, Kote-Jarai_2011, Lee_2008, Martin_2001, Sinclair_2000, Shih_2000, Schroeder_2010, Schroeder, Rajasekaran_2008). These authors suggest that the variant be classified either as a variant of unknown significance or as a benign variant. It is listed in dbSNP database as coming from a "clinical source" (ID#:rs28897706) and in the exome variant server database with a global minor allele frequency (MAF) of 0.001 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. In addition, in two studies, the variant did not segregate with the disease (Shih_2000_11106241, Sinclair_2000_10728701). This residue is not conserved in mammals and the variant amino acid Arginine (Arg) is present in chicken and computational analyses (PolyPhen, SIFT, AlignGVGD) do not predict any effect on the protein function increasing the likelihood this variant does not have functional significance. The variant is observed in the UMD database in 5 of 30 individuals who had a second pathogenic mutation identified, again increasing the likelihood this variant is benign. The variant was also identified in In summary, based on the above information, this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077475	SCV000733221	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000444014	SCV000778639	benign	not provided	2017-10-25	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120308	SCV001905943	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120308	SCV001959286	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120308	SCV002035520	benign	not specified		no assertion criteria provided	clinical testing