Submissions for variant NM_000535.7(PMS2):c.1789A>G (p.Thr597Ala)

dbSNP: rs1805318

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686207	SCV000813715	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 597 of the PMS2 protein (p.Thr597Ala). 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: 566405). 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.
Ambry Genetics	RCV001013182	SCV001173732	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.T597A variant (also known as c.1789A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1789. The threonine at codon 597 is replaced by alanine, an amino acid with 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.
GeneDx	RCV001357976	SCV003805620	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20068231, 22949387)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357976	SCV001553591	likely benign	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Thr597Ala variant was not identified in the literature. The variant was identified in dbSNP (rs1805318) as “with other allele” and ClinVar (classified as uncertain significance by Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in our laboratory in an individual with a co-occurring pathogenic PMS2 variant (c.2445+1G>C). The p.Thr597 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to 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) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.