Submissions for variant NM_000535.7(PMS2):c.608C>G (p.Thr203Ser)

gnomAD frequency: 0.00001  dbSNP: rs779946576

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166541	SCV000217342	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	The p.T203S variant (also known as c.608C>G), located in coding exon 6 of the PMS2 gene, results from a C to G substitution at nucleotide position 608. The threonine at codon 203 is replaced by serine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in several 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	RCV000509403	SCV000279133	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with endometrial cancer (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080, 11574484)
Invitae	RCV000463624	SCV000552053	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 203 of the PMS2 protein (p.Thr203Ser). This variant is present in population databases (rs779946576, gnomAD 0.0009%). 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: 186883). 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.
Color Diagnostics, LLC DBA Color Health	RCV000166541	SCV000911786	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 203 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 performed for this variant. This variant has been reported in at least one individual affected with uterine cancer (PMID: 26689913, 29684080). This variant has been identified in 2/251494 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267919	SCV002550751	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462217	SCV004205336	uncertain significance	Lynch syndrome 4	2023-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003954985	SCV004780175	uncertain significance	PMS2-related condition	2023-10-27	criteria provided, single submitter	clinical testing	The PMS2 c.608C>G variant is predicted to result in the amino acid substitution p.Thr203Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6038836-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003995510	SCV004839954	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 203 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with uterine cancer (PMID: 26689913, 29684080). This variant has been identified in 2/251494 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.
GenomeConnect, ClinGen	RCV000509403	SCV000607361	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Invitae Patient Insights Network	RCV003483547	SCV004228814	not provided	Lynch syndrome; Mismatch repair cancer syndrome 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-18-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.