Submissions for variant NM_000535.7(PMS2):c.2347G>A (p.Val783Ile)

gnomAD frequency: 0.00004  dbSNP: rs553286217

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165312	SCV000216034	likely benign	Hereditary cancer-predisposing syndrome	2018-09-29	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.
GeneDx	RCV000767022	SCV000279208	uncertain significance	not provided	2022-09-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 27863258, Fukui2011[Chapter], 33471991, 25980754)
Invitae	RCV000230774	SCV000285117	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 783 of the PMS2 protein (p.Val783Ile). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 185820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222502	SCV000601843	uncertain significance	not specified	2016-09-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000662655	SCV000785342	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000662655	SCV001137279	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222502	SCV001363168	uncertain significance	not specified	2021-03-01	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2347G>A (p.Val783Ile) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250156 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (5.6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.2347G>A has been reported in the literature in an individual being tested for Lynch Syndrome (Yurgelun_2015). The report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.7008-2A>G; Yurgelun_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000165312	SCV002530295	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000222502	SCV002550683	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662655	SCV004019824	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Color Diagnostics, LLC DBA Color Health	RCV000165312	SCV004359007	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 783 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 14/250156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354621	SCV001549282	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The PMS2 p.Val783Ile variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun_2015_25980754). The variant was also identified in dbSNP (ID: rs553286217) “With Uncertain significance allele”, ClinVar (classified likely benign by Ambry Genetics and uncertain significance by GeneDx, Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and was not identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 16 of 275380 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23840 chromosomes (freq: 0.00004), European Non-Finnish in 8 of 125530 chromosomes (freq: 0.00006), East Asian in 1 of 18756 chromosomes (freq: 0.00005), and South Asian in 6 of 30682 chromosomes (freq: 0.0002); it was not observed in the “Other”, Latino, Ashkenazi Jewish, or European Finnish populations. The variant was identified in our laboratory in 1 individual with ovarian cancer, co-occurring with a pathogenic BRCA2 variant (c.4631delA, p.Asn1544fsX24) increasing the likelihood this variant does not have clinical significance. The variant was also identified as a somatic mutation in a MSI-H/ MSH6 deficient CRC of a proband carrying a pathogenic germline MSH6 variant (c.3939_3957dup19 (p.Arg1318fs)) (Nowak_2017_ 27863258). The p.Val783 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ile impacts 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 likely benign.