Submissions for variant NM_000535.7(PMS2):c.2253T>C (p.Phe751=)

gnomAD frequency: 0.00018  dbSNP: rs1805325

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030367	SCV000108339	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030367	SCV000053034	benign	Lynch syndrome	2011-08-18	criteria provided, single submitter	clinical testing	Converted during submission to Benign.
GeneDx	RCV001711093	SCV000171038	benign	not provided	2018-12-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162407	SCV000212741	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: 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)	RCV000174490	SCV000225799	benign	not specified	2018-03-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755369	SCV000252716	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409560	SCV000488722	benign	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001711093	SCV000604893	benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000174490	SCV000806202	benign	not specified	2016-11-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000409560	SCV001322358	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000174490	SCV002069905	benign	not specified	2021-09-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162407	SCV002530278	benign	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000174490	SCV002760372	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001711093	SCV002821800	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BP7
Myriad Genetics, Inc.	RCV000409560	SCV004019873	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	RCV000162407	SCV004359028	benign	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	clinical testing
Pathway Genomics	RCV000144648	SCV000189975	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353992	SCV000592949	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	PMS2, EXON13, c.2253T>C, p.Phe751Phe, Benign (ACMG 5) The PMS2 c.2007-7C>T variant was identified in 16 of 1346 proband chromosomes (frequency: 0.012) from individuals or families with Lynch Syndrome and HNPCC (14756672_Thompson_2004, 20698049_sheng_2010). However, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs1805325) “With benign allele”, and in the “InSiGHT Colon Cancer Database”. The p.Phe751Phe 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. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000174490	SCV000691960	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000174490	SCV001799750	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000174490	SCV001807782	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000174490	SCV001964212	benign	not specified		no assertion criteria provided	clinical testing