Submissions for variant NM_000535.7(PMS2):c.2356C>A (p.Leu786Met)

gnomAD frequency: 0.00004  dbSNP: rs576055272

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131526	SCV000186520	likely benign	Hereditary cancer-predisposing syndrome	2018-05-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082079	SCV000255292	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000656951	SCV000279150	uncertain significance	not provided	2017-11-17	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2356C>A at the cDNA level, p.Leu786Met (L786M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). PMS2 Leu786Met was identified in at least one individual among a cohort of 145 patients who underwent PMS2 clinical testing, as well as in an individual with previously negative BRCA1/2 analysis (Vaughn 2010, Yadav 2016). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Leu786Met is located in the Endonuclease domain (Fukui 2011). In-silico analysis, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Leu786Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000218670	SCV000304731	likely benign	not specified		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218670	SCV000601844	benign	not specified	2017-07-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000662644	SCV000785331	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000131526	SCV000822132	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656951	SCV000892766	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	PMS2: PP2, BS2
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000131526	SCV001251935	benign	Hereditary cancer-predisposing syndrome	2020-05-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662644	SCV001322353	benign	Lynch syndrome 4	2018-07-23	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218670	SCV001361924	likely benign	not specified	2019-01-23	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2356C>A (p.Leu786Met) results in a conservative amino acid change located in the MutL, C-terminal, dimerization domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 244884 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. However, this observance needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observance of a total of 10 homozygotes does support the actual PMS2 gene being captured. c.2356C>A has been reported in the literature in individuals with a personal or family history of cancer including colorectal cancer and breast cancer (Yadav 2017, Tung 2015, Roy 2009). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as benign (2x), likely benign (1x) and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798453	SCV002042802	benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131526	SCV002530299	benign	Hereditary cancer-predisposing syndrome	2020-10-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000218670	SCV002550681	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662644	SCV004019786	likely benign	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131526	SCV004228147	benign	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131526	SCV004359005	benign	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656951	SCV001553423	likely benign	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Leu786Met variant was not identified in the literature nor was it identified in the COGR, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, and the Insight Hereditary Tumors databases. Furthermore, the variant was not identified in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs576055272) as with other allele, in the ClinVar and Clinvitae databases as benign by Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano; as likely benign by Ambry Genetics and Prevention Genetics; and as uncertain significance by GeneDx. In addition, the variant was identified in the Cosmic database 1X as pathogenic in a lobular carcinoma and in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002). The variant was further identified in control databases in 287 of 244884 chromosomes (10 homozygous) at a frequency of 0.001 increasing the likelihood that this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15242 chromosomes (freq: 0.00007), Other in 1 of 5466 chromosomes (freq: 0.0002), Latino in 3 of 33562 chromosomes (freq: 0.00009), European Non-Finnish in 15 of 110756 chromosomes (freq: 0.0001), East Asian in 1 of 17174 chromosomes (freq: 0.00006), and South Asian in 266 of 30658 chromosomes (freq: 0.009); it was not observed in the Ashkenazi Jewish and European Finnish, populations. The p.Leu786 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as likely benign.
GenomeConnect - Invitae Patient Insights Network	RCV000656951	SCV001749923	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Benign and reported on 04-07-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656951	SCV001799766	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000656951	SCV001917833	likely benign	not provided		no assertion criteria provided	clinical testing