ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1688G>T (p.Arg563Leu) (rs63750668)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076820 SCV000108307 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079105 SCV000110974 benign not specified 2013-08-22 criteria provided, single submitter clinical testing
Invitae RCV001080515 SCV000153923 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000079105 SCV000171032 benign not specified 2013-10-18 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 RCV000132121 SCV000187189 benign Hereditary cancer-predisposing syndrome 2014-11-18 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000076820 SCV000296932 benign Lynch syndrome 2015-10-20 criteria provided, single submitter clinical testing
Counsyl RCV000409245 SCV000488713 likely benign Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132121 SCV000537373 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000079105 SCV000540066 likely benign not specified 2016-04-25 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: No convincing evidence in HGMD, ExAC: 0.8% (541/66472) European chromosomes
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000409245 SCV000743780 likely benign Hereditary nonpolyposis colorectal cancer type 4 2014-10-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000079105 SCV000806185 benign not specified 2017-01-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282353 SCV000884396 benign none provided 2019-12-13 criteria provided, single submitter clinical testing
Mendelics RCV000409245 SCV001137289 likely benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034620 SCV001155029 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000409245 SCV001320991 benign Hereditary nonpolyposis colorectal cancer type 4 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Institute of Human Genetics, University of Leipzig Medical Center RCV000409245 SCV001428489 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-10-19 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034620 SCV000043424 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000079105 SCV000086050 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144651 SCV000189978 likely benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353968 SCV000592939 benign Endometrial carcinoma no assertion criteria provided clinical testing PMS2, EXON 11, c.1688G>T, p. Arg563Leu, Benign (ACMG 5) The PMS2 p.Arg563Leu variant was identified in 5 of 416 proband chromosomes (frequency: 0.012) from individuals or families with Lynch Syndrome (16472587_Hendriks_2006, 16619239_Clendenning_2006, 24027009_Drost_2014, 24689082_Hansen_2014). The variant was also identified in dbSNP (ID: rs63750668) “With likely benign, uncertain significance allele”, with a minor allele frequency of 0.003 (1000 Genomes Project), HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, and “InSiGHT Colon Cancer Database”. 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). 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 17 of 2178 chromosomes (frequency: 0.0014), and Exome Variant Server project in 86 of 8600 European American (frequency: 0.01) and 18 of 4406 African American alleles (frequency: 0.004), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Arg563 residue is not conserved in mammals and the variant amino acid Leucine (Leu) is present in Ciona intestinalis, increasing the likelihood that this variant does not have clinical significance. The p.Arg563 residue is not conserved in mammals and 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. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The DNA NOMENCLATURE 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, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000079105 SCV000691967 likely benign not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000409245 SCV000734563 likely benign Hereditary nonpolyposis colorectal cancer type 4 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000409245 SCV000745839 benign Hereditary nonpolyposis colorectal cancer type 4 2015-05-04 no assertion criteria provided clinical testing
True Health Diagnostics RCV000132121 SCV000788107 likely benign Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000034620 SCV001798367 likely benign not provided no assertion criteria provided clinical testing

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