Submissions for variant NM_000535.7(PMS2):c.2340C>T (p.Pro780=)

gnomAD frequency: 0.00117  dbSNP: rs142230276

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076852	SCV000108344	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
GeneDx	RCV000121852	SCV000171040	benign	not specified	2013-11-06	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	RCV000162402	SCV000212732	benign	Hereditary cancer-predisposing syndrome	2014-09-15	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.
Eurofins Ntd Llc (ga)	RCV000121852	SCV000226038	benign	not specified	2016-03-15	criteria provided, single submitter	clinical testing
Invitae	RCV000755367	SCV000252718	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121852	SCV000304730	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001795050	SCV000604891	benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000662626	SCV000785295	benign	Lynch syndrome 4	2017-06-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798274	SCV002042801	likely benign	Breast and/or ovarian cancer	2022-08-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121852	SCV002070565	likely benign	not specified	2021-12-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162402	SCV002530293	benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121852	SCV002550684	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662626	SCV004019874	benign	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Color Diagnostics, LLC DBA Color Health	RCV000162402	SCV004359009	benign	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	clinical testing
ITMI	RCV000121852	SCV000086054	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353527	SCV000592951	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	PMS2, Exon 14, c.2340C>T, p.Pro780Pro, Benign (ACMG 5)rnThe c.2340C>T variant was not identified in the literature. The variant was also identified in dbSNP (ID: rs142230276 )“With untested allele”, with a minor allele frequency of 0.0012 (1000 Genomes Project), HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and in the ClinVar database with 3 separate submitters as a benign/likely benign variant. The variant was classified as “unclassified” by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). The variant was identified by the Exome Variant Server project in 23 of 4392 African American alleles (frequency: 0.005), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Pro780Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.rnrnrnrnrnrnrnIn summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000121852	SCV000691959	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162402	SCV000788114	likely benign	Hereditary cancer-predisposing syndrome	2017-08-22	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121852	SCV001958160	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000121852	SCV001969472	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001795050	SCV002037057	likely benign	not provided		no assertion criteria provided	clinical testing