Submissions for variant NM_000535.7(PMS2):c.1532C>T (p.Thr511Met)

gnomAD frequency: 0.02492  dbSNP: rs74902811

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076815	SCV000108301	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Ambry Genetics	RCV000162424	SCV000212769	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.
Eurofins Ntd Llc (ga)	RCV000121845	SCV000225238	benign	not specified	2018-03-04	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000162424	SCV000267074	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121845	SCV000304722	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625103	SCV000469729	likely benign	Lynch syndrome 4	2018-02-02	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000162424	SCV000537382	benign	Hereditary cancer-predisposing syndrome	2014-11-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083434	SCV000562219	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034618	SCV000609635	benign	not provided	2017-04-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625103	SCV000743781	benign	Lynch syndrome 4	2014-10-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034618	SCV001156612	benign	not provided	2023-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000034618	SCV001900688	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 27153395, 27884173, 24027009)
Sema4, Sema4	RCV000162424	SCV002530200	benign	Hereditary cancer-predisposing syndrome	2020-08-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121845	SCV002550716	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149611	SCV003837732	benign	Breast and/or ovarian cancer	2021-06-30	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625103	SCV004016584	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076815	SCV004844190	benign	Lynch syndrome	2024-09-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121845	SCV004847562	benign	not specified	2021-06-10	criteria provided, single submitter	clinical testing	The p.Thr511Met variant in PMS2 is classified as benign because it has been identified in 8.03% (2002/24922) of African chromosomes, including 81 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). In addition, computational prediction and conservation tools suggest that this variant does not impact the protein. ACMG/AMP Criteria applied: BA1, BP4.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034618	SCV000043426	variant of unknown significance	not provided	2012-07-13	flagged submission	research	Converted during submission to Uncertain significance.
ITMI	RCV000121845	SCV000086045	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625103	SCV000745841	benign	Lynch syndrome 4	2017-06-05	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162424	SCV000788104	benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357320	SCV001552761	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Thr511Met variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs74902811) as With other allele, ClinVar (classified as benign by InSight, Ambry Genetics, Prevention Genetics, Color Genimics, Invitae; classified as likely benign by Vantary genetics, Illumina), Clinvitae (classified with conflicting interpretations of pathogenicity), MutDB , Insight Colon Cancer Gene Variant Database (2X class1), Insight Hereditary Tumors Database (2X class1), databases. The variant was not identified in Cosmic, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was identified in control databases in 2670(84 homozygous) of 277088 chromosomes at a frequency of 0.009636 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1930 of 24008 chromosomes (freq: 0.08), EastAsian in 549 of 18862 chromosomes (freq: 0.029). In cell free assay by Drost (2013) the variant not classified as repair deficient and might be pathogenic with reduced penetrance. Tthe variant classified as benign by ACMG-AMP classification for consensus variants (Amendola 2016). The p.Thr511 residue is not conserved in mammals 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. The variant occurs outside of the splicing consensus sequence and 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121845	SCV001799651	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121845	SCV001920671	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121845	SCV001959423	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162424	SCV001977063	benign	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing