Submissions for variant NM_000535.7(PMS2):c.1711C>A (p.Leu571Ile)

gnomAD frequency: 0.00784  dbSNP: rs63750055

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076821	SCV000108308	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1% in African population
GeneDx	RCV000121847	SCV000171033	benign	not specified	2013-12-07	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	RCV000162433	SCV000212780	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.
Invitae	RCV001081763	SCV000262182	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000162433	SCV000267073	likely benign	Hereditary cancer-predisposing syndrome	2016-01-22	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034621	SCV000511461	likely benign	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Genetic Services Laboratory, University of Chicago	RCV000121847	SCV000596467	benign	not specified	2017-11-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162433	SCV000686155	benign	Hereditary cancer-predisposing syndrome	2014-12-09	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121847	SCV000701855	likely benign	not specified	2016-10-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625102	SCV000743779	benign	Lynch syndrome 4	2016-03-15	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625102	SCV000745190	likely benign	Lynch syndrome 4	2016-07-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121847	SCV000806186	benign	not specified	2017-01-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034621	SCV001158695	benign	not provided	2020-02-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625102	SCV001326300	likely benign	Lynch syndrome 4	2018-04-16	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121847	SCV002550704	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625102	SCV004016582	likely benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034621	SCV000043423	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121847	SCV000086047	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000162433	SCV000788108	benign	Hereditary cancer-predisposing syndrome	2017-11-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357078	SCV001552416	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Leu571Ile variant was identified 5 of 2018 proband chromosomes (frequency: 0.002) from Dutch and American individuals or families with Lynch Syndrome, suspected Lynch Syndrome, or individuals being ascertained for atherosclerosis phenotypes (van der Klift 2016, Johnston 2012, Clendenning 2006). The variant was identified in the following databases: dbSNP (ID: rs63750055) as “other”, ClinVar (classified as likely benign, reviewed by an expert panel; classified as likely benign by InSIGHT, Vantari Genetics, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics; benign by GeneDx, Ambry Genetics, Invitae; uncertain significance by Biesecker Lab/Human Development Section-NIH; and classification not provided by ITMI), Clinvitae (4X), Insight Colon Cancer Gene Variant Database (3X), and Insight Hereditary Tumors Database; but was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database and the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 760 (10 homozygous) of 277148 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following population at a frequency greater than 1%: African in 506 (10 homozygous) of 23994 chromosomes (freq: 0.021). The p.Leu571 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. The variant was identified by our laboratory in an individual with a co-occurring pathogenic variant (PMS2, c.2276-?_2445+?del), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034621	SCV001797961	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034621	SCV001808050	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034621	SCV001917463	likely benign	not provided		no assertion criteria provided	clinical testing