Submissions for variant NM_000535.7(PMS2):c.299A>G (p.Gln100Arg)

dbSNP: rs747771951

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758690	SCV000887463	benign	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	PMS2 NM_000535.5:c.299A>G has a 0.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Invitae	RCV001857068	SCV002212977	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 100 of the PMS2 protein (p.Gln100Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 434026). 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. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 35451539). 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.
Ambry Genetics	RCV002438213	SCV002747028	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	clinical testing	The p.Q100R variant (also known as c.299A>G), located in coding exon 4 of the PMS2 gene, results from an A to G substitution at nucleotide position 299. The glutamine at codon 100 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355159	SCV001549954	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PMS2 p. variant was not identified in the literature nor was it identified in the 1000 Genomes Project, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and ClinVar database.The p.Gln100 residue is not conserved in mammals but the variant amino acid Arginine (Arg) is not present in other animals, which does not verify this variant as not having clinical significance. Although the p.Gln100 residue is not conserved in mammals and lower organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gln100Arg variant may not impact the protein. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein.The c.299GA>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) 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 predicted benign.