Submissions for variant NM_000059.4(BRCA2):c.6853A>G (p.Ile2285Val)

gnomAD frequency: 0.00026  dbSNP: rs56272235

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031652	SCV000244469	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 = 0.00000000026
Invitae	RCV000045081	SCV000073094	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000031652	SCV000154056	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
Ambry Genetics	RCV000162602	SCV000213026	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.
Pathway Genomics	RCV000031652	SCV000223765	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031652	SCV000267800	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000045081	SCV000296857	benign	Hereditary breast ovarian cancer syndrome	2015-10-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000031652	SCV000575758	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000501461	SCV000602879	benign	not specified	2018-07-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162602	SCV000683823	benign	Hereditary cancer-predisposing syndrome	2014-12-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031652	SCV000743325	likely 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	RCV000031652	SCV000744502	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000031652	SCV001139159	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031652	SCV001268136	likely 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). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798051	SCV002043380	benign	Breast and/or ovarian cancer	2019-07-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000501461	SCV002067142	likely benign	not specified	2018-06-07	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045081	SCV002504858	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162602	SCV002536275	benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000501461	SCV002551424	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034457	SCV002822074	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031652	SCV004016894	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	RCV000034457	SCV000043224	variant of unknown significance	not provided	2012-07-13	flagged submission	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031652	SCV000054259	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-01-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031652	SCV000146965	uncertain significance	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	RCV000501461	SCV000592079	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Ile2285Val variant was identified in 17 of 1950 proband chromosomes (frequency: 0.009) from individuals or families with breast or ovarian cancer and was present in 10 of 950 control chromosomes (frequency: 0.01) from healthy individuals (Ding 2011, Li 2009, Shih 2000). The variant was also identified in dbSNP (ID: rs56272235) as "With other allele", ClinVar (classified as benign by Invitae and 10 other submitters; as likely benign by three submitters; as uncertain significance by BIC and one other submitter), COGR, MutDB, LOVD 3.0 (13x as benign or likely benign), UMD-LSDB (10x as likely neutral), BIC Database (80x with unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in the Cosmic or Zhejiang University databases. The variant was identified in control databases in 104 of 273028 chromosomes (1 homozygous) at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 89 of 9928 chromosomes (freq: 0.009), Other in 5 of 6360 chromosomes (freq: 0.0008), Latino in 4 of 33852 chromosomes (freq: 0.0001), European in 5 of 125038 chromosomes (freq: 0.00004), and South Asian in 1 of 29758 chromosomes (freq: 0.00003); it was not observed in the African, East Asian, or Finnish populations. The p.Ile2285 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, several functional studies have predicted that this variant is neutral (Tavtigian 2006, Easton 2007, Frank 2002, Guidugli 2014, Lindor 2012). This variant has also been identified as co-occurring with pathogenic variants in BRCA2: c.5946delT, p.S1982Rfs*22 (Li 2009) and c.2957dupA, p.Asn986Lysfs*2 (this laboratory), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000501461	SCV001959659	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045081	SCV001977052	likely benign	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031652	SCV004243739	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing