Submissions for variant NM_000059.4(BRCA2):c.8851G>A (p.Ala2951Thr)

gnomAD frequency: 0.00809  dbSNP: rs11571769

Total submissions: 44

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114009	SCV000321230	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-28	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.036 (Admixed American/Latino), 0.0215 (South Asian), derived from 1000 genomes (2013-05-02).
Invitae	RCV000045643	SCV000073656	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000114009	SCV000154050	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000120367	SCV000167416	benign	not specified	2013-10-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000128883	SCV000172740	benign	Hereditary cancer-predisposing syndrome	2014-08-01	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000114009	SCV000196019	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Pathway Genomics	RCV000114009	SCV000223768	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120367	SCV000227874	benign	not specified	2015-07-30	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000128883	SCV000267027	benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000045643	SCV000296861	benign	Hereditary breast ovarian cancer syndrome	2015-10-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768611	SCV000324842	benign	Breast and/or ovarian cancer	2016-01-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000114009	SCV000383795	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-29	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	RCV000322663	SCV000383796	likely benign	Fanconi anemia complementation group D1	2018-01-29	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045643	SCV000494370	benign	Hereditary breast ovarian cancer syndrome	2014-02-04	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034468	SCV000510683	benign	not provided	2016-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128883	SCV000537387	benign	Hereditary cancer-predisposing syndrome	2014-12-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120367	SCV000538465	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: ExAC: 3.5% (402/11526) Latino chromosomes
Baylor Genetics	RCV000476344	SCV000541045	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000114009	SCV000575751	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-07	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120367	SCV000586986	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034468	SCV000602773	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000114009	SCV000743355	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	RCV000114009	SCV000744552	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120367	SCV000805788	benign	not specified	2016-10-31	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045643	SCV002025863	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000045643	SCV002515159	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000128883	SCV002531981	benign	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034468	SCV002545115	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: PM5, BP4, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120367	SCV002551835	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000114009	SCV002556904	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-25	criteria provided, single submitter	clinical testing	The BRCA2 c.8851G>A variant is classified as Benign
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153321	SCV003843720	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000114009	SCV004016828	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034468	SCV000043234	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120367	SCV000084519	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114009	SCV000147474	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000114009	SCV000189319	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001281077	SCV000592234	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ala2951Thr variant has been reported in our laboratory as well as in the literature in 36/5864 (0.006 frequency) proband chromosomes and in 1/1018 control chromosomes (0.001 frequency) (Bergthorsson_2001_11389159, Borg_2010_20104584, Saxena_2006_17018160, Lin_2003_12815053, Spitzer_2000_10699917, Serova-Sinilnikova_1997_9150172, Weber_2006_16685647, Wagner_1999_9971877, Waddell_2008_18497862). It is listed in dbSNP database (ID#:rs11571769) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. The p.Ala2951 residue is conserved across vertebrate species, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the p.Ala2951Thr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In one study, this variant did not co-segregate with cancer in three families, and its frequency in 4680 clinical samples was similar to that of the control population (Deffenbaugh_2002_12215251). Notably, this variant has been identified in the UMD database in a total of 15 individuals who had a second pathogenic variant (9 with BRCA2 mutations and 6 with BRCA1) and associated with a breast or ovarian cancer phenotype, increasing the likelihood that the p.Ala2951Thr variant does not have clinical significance. In addition, Myriad calls this variant as a polymorphism. In summary, based on the above information this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000114009	SCV000733327	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034468	SCV000778721	likely benign	not provided	2017-03-30	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128883	SCV000787957	benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001281077	SCV001451692	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120367	SCV001799522	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120367	SCV001906216	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120367	SCV001952725	benign	not specified		no assertion criteria provided	clinical testing