Submissions for variant NM_000535.7(PMS2):c.197T>C (p.Ile66Thr)

gnomAD frequency: 0.00004  dbSNP: rs769554577

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165451	SCV000216181	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-06	criteria provided, single submitter	clinical testing	The p.I66T variant (also known as c.197T>C), located in coding exon 3 of the PMS2 gene, results from a T to C substitution at nucleotide position 197. The isoleucine at codon 66 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in a Dutch individual with colorectal cancer diagnosed at age 47 whose tumor showed low microsatellite instability (MSI-L) and weak PMS2 staining on immunohistochemical analysis, and this alteration was found to have somewhat reduced mismatch repair activity compared to the wildtype PMS2 protein (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000197855	SCV000254610	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 66 of the PMS2 protein (p.Ile66Thr). This variant is present in population databases (rs769554577, gnomAD 0.005%). This missense change has been observed in individual(s) with colorectal cancer and ovarian and breast cancer (PMID: 27435373; Invitae). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in PMS2 in at least one individual (PMID: 27435373; Invitae), which suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 185939). 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%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 27435373). 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.
GeneDx	RCV000759917	SCV000279266	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Observed in at least one patient with colorectal cancer and was demonstrated to have proficient mismatch repair efficiency in an in vitro assay (van der Klift et al., 2016).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27435373, 11574484, 34172528)
Color Diagnostics, LLC DBA Color Health	RCV000165451	SCV000686172	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 66 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. This variant has been reported in individuals affected with colorectal cancer (PMID: 27435373, 34172528). A functional study showed that the variant protein had intermediate activity in an in vitro mismatch repair assay (PMID: 27435373). This variant has been identified in 6/282110 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in healthy individuals (PMID: 32980694). 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.
Counsyl	RCV000662452	SCV000784925	uncertain significance	Lynch syndrome 4	2017-02-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759917	SCV000889615	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759917	SCV001155038	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PMS2: PM2, PS3:Supporting, BP1
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000662452	SCV002584755	uncertain significance	Lynch syndrome 4	2022-07-21	criteria provided, single submitter	clinical testing	The PMS2 c.197T>C (p.Ile66Thr) missense change has a maximum subpopulation frequency of 0.005% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and a functional study investigating mismatch repair proficiency demonstrated that this variant has intermediate relative repair efficiency compared to the wild-type (PMID: 27435373). This variant has been reported in an individual with colorectal cancer whose tumor showed weak PMS2 staining on immunohistochemistry and did not show microsatellite instability (PMID: 27435373). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150022	SCV003838399	uncertain significance	Breast and/or ovarian cancer	2022-01-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662452	SCV004019829	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662452	SCV004205366	uncertain significance	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995419	SCV004842146	uncertain significance	Lynch syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 66 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. This variant has been reported in individuals affected with colorectal cancer (PMID: 27435373, 34172528). A functional study showed that the variant protein had intermediate activity in an in vitro mismatch repair assay (PMID: 27435373). This variant has been identified in 6/282110 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in healthy individuals (PMID: 32980694). 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.