Submissions for variant NM_000535.7(PMS2):c.736C>A (p.Pro246Thr)

dbSNP: rs765668173

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187832	SCV001354718	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 246 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 PMS2-related disorders in the literature. This variant has been identified in 5/247584 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.
Invitae	RCV001319377	SCV001510119	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 246 of the PMS2 protein (p.Pro246Thr). This variant is present in population databases (rs765668173, gnomAD 0.02%). 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: 434028). 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 expected to disrupt PMS2 protein function with a positive 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.
Ambry Genetics	RCV001187832	SCV004005573	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	The p.P246T variant (also known as c.736C>A), located in coding exon 7 of the PMS2 gene, results from a C to A substitution at nucleotide position 736. The proline at codon 246 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338618	SCV004048486	uncertain significance	Lynch syndrome 4		criteria provided, single submitter	clinical testing	The missense variant c.736C>A (p.Pro246Thr) in PMS2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain significance.The p.Pro246Thr variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00002020 is reported in gnomAD. The amino acid Pro at position 246 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Pro246Thr in PMS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance .
All of Us Research Program, National Institutes of Health	RCV004003522	SCV004839922	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 246 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 PMS2-related disorders in the literature. This variant has been identified in 5/247584 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	RCV000499932	SCV000592928	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The p.Pro246Thr variant was not identified in the literature nor was it identified in the GeneInsight, HGMD, COSMIC, Mut, MMR, InSiGHT Colon Cancer and ClinVar databases. The p.Pro246 residue is conserved/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. Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein.The p.Pro246Thr variant is predicted to cause a missense mutation, which has an unknown impact on the protein. In summary, based on the above information this variant meets our laboratory's criteria to be classified as a VARIANT OF UNKNOWN SIGNIFICANCE.