ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6853A>G (p.Ile2285Val) (rs56272235)

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Total submissions: 18
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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 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 and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000031652 SCV000154056 likely benign Breast-ovarian cancer, familial 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 2 2014-10-30 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031652 SCV000267800 benign Breast-ovarian cancer, familial 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 and ovarian cancer syndrome 2015-10-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000031652 SCV000575758 likely benign Breast-ovarian cancer, familial 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 Health, Inc 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 2 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031652 SCV000744502 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000031652 SCV001139159 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031652 SCV001268136 likely benign Breast-ovarian cancer, familial 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.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034457 SCV000043224 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031652 SCV000054259 benign Breast-ovarian cancer, familial 2 2008-01-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031652 SCV000146965 uncertain significance Breast-ovarian cancer, familial 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.

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