Submissions for variant NM_000059.4(BRCA2):c.8182G>A (p.Val2728Ile)

gnomAD frequency: 0.00239  dbSNP: rs28897749

Total submissions: 41

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113882	SCV001161619	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	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 = 0.000345
Invitae	RCV000045443	SCV000073456	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113882	SCV000154049	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000120362	SCV000167408	benign	not specified	2013-10-21	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113882	SCV000196012	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120362	SCV000202302	benign	not specified	2014-02-10	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000045443	SCV000212197	benign	Hereditary breast ovarian cancer syndrome	2015-03-11	criteria provided, single submitter	research
Ambry Genetics	RCV000162583	SCV000212999	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.
Vantari Genetics	RCV000162583	SCV000267025	benign	Hereditary cancer-predisposing syndrome	2016-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113882	SCV000383779	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000034462	SCV000493633	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045443	SCV000494363	benign	Hereditary breast ovarian cancer syndrome	2014-09-24	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120362	SCV000586980	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120362	SCV000593731	likely benign	not specified	2016-07-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034462	SCV000602816	benign	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162583	SCV000679725	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162583	SCV000683949	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113882	SCV000743345	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	RCV000113882	SCV000744537	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891462	SCV000805775	benign	BRCA2-related condition	2021-04-19	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mendelics	RCV000113882	SCV001139208	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001114098	SCV001271931	likely benign	Fanconi anemia complementation group D1	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034462	SCV002010311	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	RCV000045443	SCV002025846	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798059	SCV002043523	benign	Breast and/or ovarian cancer	2020-04-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162583	SCV002531919	benign	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120362	SCV002551790	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504866	SCV002808356	likely 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	2021-09-02	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034462	SCV000043229	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
ITMI	RCV000120362	SCV000084514	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113882	SCV000147293	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000113882	SCV000187731	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000148414	SCV000190113	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353716	SCV000592177	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Val2728Ile variant was identified in 26 of 7026 proband chromosomes (frequency: 0.004) from individuals or families with breast, prostate or melanoma cancers, and was present in 4 of 1852 control chromosomes (frequency: 0.002) from healthy individuals (Sinilnikova 1999, Diez 2003, Haffy 2006, Luedeke 2009, Capanu 2011, Kuusisto 2011, Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rs28897749 “With Other, untested allele”, in NHLBI Exome Sequencing Project (Exome Variant Server) in 39 of 8600 European American and 4 of 4406 African American; in HAPMAP-CEU in 2 of 224 chromosomes (frequency: 0.009) and in HAPMAP-MEX in 3 of 98 chromosomes(frequency: 0.031). In Exome Aggregation Consortium (ExAC) database the variant is found in 216 of 66738 (I homozygote) European (Non-Finnish), 18 of 6614 European (Finnish), 10 of 10404 African, 2 of 11576 Latino and 1 in 908 in Other alleles, increasing the likelihood this could be a low frequency benign variant. The variant was not found in East Asian and South Asian. The variant was identified in LOVD (7x predicted neutral), the ClinVar database (classified as a Benign variant by Invitae (Jun26, 2015), GeneDx (Oct21, 2013), Emory Genetics (Feb10, 2014), Ambry Genetics (Nov19, 2014), Molecular Genetics Diagnostic-CHEO, BIC (May29, 2002) and as Likely Benign by Counsyl (Jan02, 2014), Pathway Genomics (Jul24, 2014), CSER-University of Washington (Jun01, 2014), Biesecker Lab ClinSeq Project (Jul13, 2012); no classification was provided by ITMI. The variant was reported in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (2X, classified as “benign” by 2 clinical laboratories), the BIC database (92X with NO clinical importance), and UMD (95X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2:c.1257delT (p.Cys419TrpfsX11), c.7230delT (p.Phe2410LeufsX59), c.6209_6212delAAAG (p.Glu2070ValfsX10), and BRCA1:c.5123C>A (p.Ala1708Glu), c.2308delT (p.Ser770HisfsX22), c.4065_4068delTCAA (p.Asn1355LysfsX10), c.5137delG (p.Val1713X), increasing the likelihood that the p.Val2728Ile variant does not have clinical significance. In addition, Myriad classifies this as a polymorphism (personal communication). The Val2728 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In addition, the variant amino acid Ile (isoleucine) is present in other mammals and lower organisms increasing the likelihood that this variant does not have clinical significance. Overrepresentation of this variant had conferred 2.3-fold increased risk for sporadic prostate cancer and a 6-fold increased risk for familial prostate cancers, however larger sample sizes and replication studies are necessary to clarify the role of the variant in prostate cancer (Luedeke 2009). The c.8182G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113882	SCV000733316	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034462	SCV000778718	benign	not provided	2017-03-08	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162583	SCV000787953	likely benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034462	SCV001799045	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120362	SCV001906143	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120362	SCV001956346	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113882	SCV004243807	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing