ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1866G>A (p.Met622Ile) (rs1805324)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076832 SCV000108319 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Invitae RCV001083359 SCV000153961 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000121850 SCV000171035 benign not specified 2013-10-14 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 RCV000131477 SCV000186464 benign Hereditary cancer-predisposing syndrome 2017-12-08 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;In silico models in agreement (benign)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000076832 SCV000257702 benign Lynch syndrome 2015-06-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131477 SCV000292103 benign Hereditary cancer-predisposing syndrome 2014-11-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121850 SCV000304725 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000615283 SCV000469725 likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121850 SCV000540063 benign not specified 2016-03-28 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: High frequency
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000615283 SCV000743777 likely 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 RCV000615283 SCV000745189 benign Hereditary nonpolyposis colorectal cancer type 4 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000615283 SCV000745837 benign Hereditary nonpolyposis colorectal cancer type 4 2015-10-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282351 SCV000884395 benign none provided 2020-09-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262164 SCV001439937 benign Neoplasm of ovary 2019-01-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034623 SCV000043417 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121850 SCV000086051 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353875 SCV000592941 benign Endometrial carcinoma no assertion criteria provided clinical testing PMS2, Exon 11, c.1866G>A, p.Met622Ile, Benign, ACMG 5rnThe c.1866G>A variant was identified 10 times in 1950 proband chromosomes in the literature. This variant was found in tumors that are positive for microsatellite instability, negative for immunohistocompatibility complexes and negative for the BRAF gene (17312306_lagerstedt_robinson_2007). It was also found to be negative for PMS2 staining in two independent research papers (15256438_nakagawa_2004, 16472587_hendriks_2006)) and to be MLH1, MSH2, and MSH6 positive (15256438_nakagawa_2004). Berginc found that this missense change is in a region responsible for the interaction of PMS2 with MLH1 and it reduces binding to MLH1 in functional analysis. It was not found in healthy controls (19526325_berginc_2009). In all the literature it was speculated not to be pathogenic (24689082_Hansen_2014, 22949387_thompson_2013, 19526325_berginc_2009, 17312306_lagerstedt_robinson_2007, 16472587_hendriks_2006, 15256438_nakagawa_2004, 11793469_yuan_2002) rnThe variant was also identified in dbSNP (ID: rs1805324) “With untested allele”, with a minor allele frequency of 0.0082 (1000 Genomes Project), HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, and ClinVar database as a benign/likely benign variant. It was submitted to ClinVar 6 times by single and independent submitters as a benign variant. rnThis variant was identified in the 1000 Genomes Project in 32 of 2178 chromosomes (frequency: 0.0147), Exome Variant Server project in 182 of 8600 European American (frequency: 0.021) and 23 of 4406 African American alleles (frequency: 0.0052), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin.rnThe p.Met622 residue is not conserved in mammals and five 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. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein.rnThe c.1866G>A 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.)rnIn summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000121850 SCV000691964 benign not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000615283 SCV000734562 benign Hereditary nonpolyposis colorectal cancer type 4 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131477 SCV000788112 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000121850 SCV001798352 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000121850 SCV001905809 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000121850 SCV001922233 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000121850 SCV001952606 benign not specified no assertion criteria provided clinical testing

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