ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1531A>G (p.Thr511Ala) (rs2228007)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076814 SCV000108300 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Invitae RCV001083612 SCV000153912 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000121839 SCV000171027 benign not specified 2013-09-03 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 RCV000130845 SCV000185743 benign Hereditary cancer-predisposing syndrome 2014-10-14 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121839 SCV000225235 benign not specified 2014-10-28 criteria provided, single submitter clinical testing
Vantari Genetics RCV000130845 SCV000267075 likely benign Hereditary cancer-predisposing syndrome 2015-12-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130845 SCV000292101 benign Hereditary cancer-predisposing syndrome 2014-11-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121839 SCV000304721 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625104 SCV000469730 likely benign Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000625104 SCV000743782 benign Hereditary nonpolyposis colorectal cancer type 4 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000625104 SCV000745191 benign Hereditary nonpolyposis colorectal cancer type 4 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000625104 SCV000745842 benign Hereditary nonpolyposis colorectal cancer type 4 2015-11-22 criteria provided, single submitter clinical testing
Counsyl RCV000625104 SCV000785347 benign Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282356 SCV001156613 benign none provided 2020-04-24 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034617 SCV000043427 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121839 SCV000086037 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353895 SCV000592936 benign Endometrial carcinoma no assertion criteria provided clinical testing PMS2, EXON11, c.1531A>G, p.Thr511Ala, Benign (ACMG 5) The c.1531A>G variant was identified in 6 of 368 proband chromosomes (frequency: 0.016) from individuals or families with HNPCC and Lynch syndrome; however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was present in individuals that tested immunohistocompatibility PMS2 negative but positive for MLH1, MSH2 and MSH 6. Tumours were also found to be microsatellite instability high. (10479499_Basil_1999, 15256438_Nakagawa, 16619239_Clenndening_2006, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs2228007) “With untested allele”, with a minor allele frequency of 0.011 (1000 Genomes Project), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, and ClinVar database as a benign variant.The variant was classified as a benign/likely benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) with 6 separate submitters. The variant was classified as “unclassified” by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). This variant was identified in the 1000 Genomes Project in 26 of 2178 chromosomes (frequency: 0.0119), Exome Variant Server project in 270 of 13006 European American/African American alleles (frequency: 0.02), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Thr511 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques and Trichoplax adhaerens, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity but it increases the likelihood that this variant does not have clinical significance. The c.1531A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, the clinical significance of this variant satisfies our laboratory requirements as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000121839 SCV000691971 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000130845 SCV000788103 benign Hereditary cancer-predisposing syndrome 2018-02-05 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000121839 SCV001797728 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000121839 SCV001906405 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000121839 SCV001923712 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000121839 SCV001951347 benign not specified no assertion criteria provided clinical testing

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