Submissions for variant NM_000535.7(PMS2):c.2036T>C (p.Ile679Thr)

gnomAD frequency: 0.00001  dbSNP: rs778251286

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220917	SCV000273385	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-21	criteria provided, single submitter	clinical testing	The p.I679T variant (also known as c.2036T>C), located in coding exon 12 of the PMS2 gene, results from a T to C substitution at nucleotide position 2036. The isoleucine at codon 679 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an individual diagnosed with colorectal cancer at age 50 that had intact immunohistochemistry staining for all four mismatch repair proteins and whose family history met revised Bethesda guidelines (Carneiro da Silva F et al. PLoS ONE, 2015 Oct;10:e0139753). 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229051	SCV000285099	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	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 679 of the PMS2 protein (p.Ile679Thr). 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 (PMID: 26437257, 28874130). ClinVar contains an entry for this variant (Variation ID: 229989). 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.
GeneDx	RCV000589548	SCV000566456	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer whose tumor revealed normal mismatch repair immunohistochemistry (Carneiro da Silva et al., 2015); This variant is associated with the following publications: (PMID: 26437257, 28874130)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589548	SCV000697325	uncertain significance	not provided	2017-01-19	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.2036T>C (p.Ile679Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/44144 control chromosomes at a frequency of 0.0000227, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in one patient with suspected LS, however without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl	RCV000662646	SCV000785333	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798712	SCV002042793	uncertain significance	Breast and/or ovarian cancer	2021-04-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662646	SCV004019841	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320608	SCV004025107	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000662646	SCV005056471	uncertain significance	Lynch syndrome 4	2023-12-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589548	SCV005625896	uncertain significance	not provided	2024-07-04	criteria provided, single submitter	clinical testing	The PMS2 c.2036T>C (p.Ile679Thr) variant has been reported in the published literature in an individual with colon cancer (PMID: 26437257 (2015)). In a large scale breast cancer association study, this variant has been reported in an individual affected with breast cancer as well as a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). The frequency of this variant in the general population, 0.000005 (1/200150 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.