Submissions for variant NM_000535.7(PMS2):c.1789A>T (p.Thr597Ser)

gnomAD frequency: 0.01006  dbSNP: rs1805318

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000144655	SCV000108314	benign	Lynch syndrome 1	2014-10-10	reviewed by expert panel	research	MAF >1%
Invitae	RCV001080576	SCV000153971	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121842	SCV000171034	benign	not specified	2013-11-11	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	RCV000129319	SCV000184082	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.
Eurofins Ntd Llc (ga)	RCV000121842	SCV000225236	benign	not specified	2014-06-24	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000129319	SCV000267072	benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121842	SCV000304724	benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000412079	SCV000488727	benign	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129319	SCV000537366	benign	Hereditary cancer-predisposing syndrome	2014-11-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000412079	SCV000743778	likely benign	Lynch syndrome 4	2016-03-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034622	SCV001156611	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000412079	SCV001326299	likely benign	Lynch syndrome 4	2018-01-24	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034622	SCV002545494	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121842	SCV002550703	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000412079	SCV004016595	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412079	SCV004044343	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034622	SCV000043421	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000121842	SCV000086040	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144655	SCV000189982	likely benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000121842	SCV000691966	likely benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000412079	SCV000745838	benign	Lynch syndrome 4	2016-06-20	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000129319	SCV000788110	benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357844	SCV001553433	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Thr597Ser variant was identified in 27 of 746 proband chromosomes (frequency: 0.036) from Dutch, American, British and French individuals or families with HNPCC, early-onset CRC, MAP or breast cancer and was identified in 37 of 1922 chromosomes (frequency: 0.02) from healthy individuals (Hendriks 2006, Balogh 2006, Lefevre 2012). The variant was also identified in dbSNP (ID: rs1805318) as "With Likely benign allele", ClinVar (classified 10x as benign: InSiGHT, Invitae, GeneDx, Ambry Genetics, Emory Genetics Laboratory, Vantari Genetics, PreventionGenetics, Counsyl, Color Genomics, Biesecker Lab/NIH; 1x likely benign: Pathway Genomics; 1x not provided: ITMI), Clinvitae (7x), MutDB (UniProt Category: Polymorphism), Insight Colon Cancer Gene Variant Database (12x not pathogenic), and the Mismatch Repair Genes Variant Database (3x). The variant was not identified in GeneInsight-COGR, COSMIC, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 2380 of 277222 chromosomes (15 homozygous) at a frequency of 0.009 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%: European (Non-Finnish) in 1893 of 126716 chromosomes (freq: 0.015) Functional data suggest conflicting effects for this variant. An in vitro pull-down assay demonstrating that this SNP results in defective protein-protein interaction with MLH1, despite the fact that the alteration is outside the putative MLH1 interaction domain, suggests an increased risk factor for tumourigenesis in HNPCC. However, a cell-free MMR functional assay of VUS in PMS2 using MLH1/PMS2 heterodimer to restore a plasmid restriction enzyme site demonstrated 70% activity and was not considered MMR-deficient relative to known pathogenic controls. The p.Thr597Ser 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. 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)	RCV000121842	SCV001798033	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121842	SCV001906297	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121842	SCV001921976	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121842	SCV001958881	benign	not specified		no assertion criteria provided	clinical testing