Submissions for variant NM_000535.7(PMS2):c.2288A>G (p.Glu763Gly)

gnomAD frequency: 0.00003  dbSNP: rs587780052

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235199	SCV000149590	uncertain significance	not provided	2021-10-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27997540, 21552516)
Ambry Genetics	RCV000115681	SCV000185909	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	The p.E763G variant (also known as c.2288A>G), located in coding exon 14 of the PMS2 gene, results from an A to G substitution at nucleotide position 2288. The glutamic acid at codon 763 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well 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.
Invitae	RCV000457397	SCV000552018	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 763 of the PMS2 protein (p.Glu763Gly). 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 127777). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000235199	SCV000888404	uncertain significance	not provided	2019-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000235199	SCV001155024	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	PMS2: BP4
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262165	SCV001439938	uncertain significance	Lynch syndrome 4	2019-01-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235199	SCV002009097	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115681	SCV002530282	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Baylor Genetics	RCV001262165	SCV004205376	uncertain significance	Lynch syndrome 4	2023-10-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115681	SCV004359019	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 763 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/281020 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	RCV000235199	SCV001549783	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.E763G variant was not identified in the literature but was identified in dbSNP (ID: rs587780052) and ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Quest Diagnostics and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 3 of 266546 chromosomes (1 homozygous) at a frequency of 0.00001126 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the European (non-Finnish) population in 3 of 116982 chromosomes (freq: 0.000026), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.E763 residue is 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) 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 a variant of uncertain significance.