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

dbSNP: rs63750668

Total submissions: 38

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
Eurofins Ntd Llc (ga)	RCV000079105	SCV000110974	benign	not specified	2013-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080515	SCV000153923	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	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: seen in unaffected individuals, 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	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132121	SCV000537373	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	Lynch syndrome 4	2014-10-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079105	SCV000806185	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034620	SCV000884396	benign	not provided	2023-11-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000409245	SCV001137289	likely benign	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034620	SCV001155029	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BS2
Illumina Laboratory Services, Illumina	RCV000409245	SCV001320991	benign	Lynch syndrome 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	Lynch syndrome 4	2018-10-19	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034620	SCV002009110	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798065	SCV002042788	likely benign	Breast and/or ovarian cancer	2021-04-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000079105	SCV002069907	benign	not specified	2020-07-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132121	SCV002530217	benign	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079105	SCV002550705	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224115	SCV003920333	benign	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-09-12	criteria provided, single submitter	clinical testing	This variant has been reported in association with cancer (Clendenning 2006 PMID: 16619239). This variant is present in the Genome Aggregation Database (Highest reported MAF: 1.0% [157/15246], and in 3 homozygotes; https://gnomad.broadinstitute.org/variant/7-5987077-C-A?dataset=gnomad_r3). This variant is also present in ClinVar, with numerous laboratories classifying it as benign or likely benign, including as likely benign by the InSiGHT expert panel (Variation ID: 41705). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, this variant is classified as benign.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000409245	SCV004016591	likely benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409245	SCV004044332	benign	Lynch syndrome 4	2023-05-11	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
All of Us Research Program, National Institutes of Health	RCV000076820	SCV004844154	benign	Lynch syndrome	2024-09-27	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034620	SCV005224540	likely benign	not provided		criteria provided, single submitter	not provided
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 1	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	Lynch syndrome 4		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000409245	SCV000745839	benign	Lynch syndrome 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
Clinical Genetics, Academic Medical Center	RCV000034620	SCV001920777	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034620	SCV001953076	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000034620	SCV001977631	likely benign	not provided		no assertion criteria provided	clinical testing