Submissions for variant NM_000535.7(PMS2):c.2187C>G (p.Leu729=)

gnomAD frequency: 0.00077  dbSNP: rs373630535

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127465	SCV000171037	benign	not specified	2013-12-31	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	RCV000162439	SCV000212788	likely benign	Hereditary cancer-predisposing syndrome	2014-06-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV001079494	SCV000252715	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000197459	SCV000257703	likely benign	Lynch syndrome	2015-03-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000127465	SCV000596466	likely benign	not specified	2016-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590780	SCV000697340	benign	not provided	2016-02-15	criteria provided, single submitter	clinical testing	Variant summary: The c.2187C>G variant affects a non-conserved nucleotide, resulting in no amino acid change. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 106/81156 control chromosomes (5 homozygotes) at a frequency of 0.0013061, which is about 11 times of maximal expected frequency of a pathogenic allele (0.0001136). Even considering the possibility that these occurrences may be from a PMS2 pseudogene, 5 homozygotes found in controls suggest this variant is benign. In addition, multiple clinical laboratories classified this variant as benign/likely benign. The variant of interest has not been evaluated for functional impact by in vivo/in vitro studies. Taken together, this variant was classified as benign.
Counsyl	RCV000662897	SCV000785817	likely benign	Lynch syndrome 4	2017-12-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000127465	SCV000806201	benign	not specified	2017-02-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590780	SCV000888401	benign	not provided	2022-09-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590780	SCV001155026	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BP7, BS2
Illumina Laboratory Services, Illumina	RCV000662897	SCV001322359	uncertain significance	Lynch syndrome 4	2018-02-28	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798426	SCV002042798	likely benign	Breast and/or ovarian cancer	2022-10-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162439	SCV002530271	benign	Hereditary cancer-predisposing syndrome	2020-12-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000127465	SCV002550690	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162439	SCV002819194	benign	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662897	SCV004019785	benign	Lynch syndrome 4	2023-04-04	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	RCV000162439	SCV004359034	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355979	SCV001551019	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Leu729= variant was not identified in the literature nor was it identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database. The variant was identified in dbSNP (ID: rs373630535) as “With other allele”, ClinVar (as benign by GeneDx and Invitae, and as likely benign by Ambry Genetics, Children's Hospital of Philadelphia, and University of Chicago), Clinvitae (3x), Insight Colon Cancer Gene Variant Database (1x with no classification), and Insight Hereditary Tumors Database. The variant was identified in control databases in 235 of 231538 chromosomes at a frequency of 0.0010 in the following populations: African in 1 of 13584 chromosomes (freq. 0.00007), Other in 2 of 5242 chromosomes (freq. 0.0004), Latino in 16 of 32934 chromosomes (freq. 0.0005), European (Non-Finnish) in 115 (7 homozygous) of 102664 chromosomes (freq. 0.001), European (Finnish) in 1 of 21426 chromosomes (freq. 0.00005), and South Asian in 100 (3 homozygous) of 29508 chromosomes (freq. 0.003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu729= 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590780	SCV001808383	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000127465	SCV001959909	benign	not specified		no assertion criteria provided	clinical testing