Submissions for variant NM_000535.7(PMS2):c.161T>C (p.Ile54Thr)

dbSNP: rs764565924

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579717	SCV000686146	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-29	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 54 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with constitutional mismatch repair deficiency syndrome and early-onset colorectal cancer (PMID: 26318770, 31992580). This variant has been identified in 4/245728 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.
Ambry Genetics	RCV000579717	SCV001172913	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	The p.I54T variant (also known as c.161T>C), located in coding exon 2 of the PMS2 gene, results from a T to C substitution at nucleotide position 161. The isoleucine at codon 54 is replaced by threonine, an amino acid with similar properties. This variant has been identified in a patient with CMMRD along with a known PMS2 mutation (Lavoine N et al. J Med Genet, 2015 Nov;52:770-8). 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	RCV001241091	SCV001414085	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-29	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 54 of the PMS2 protein (p.Ile54Thr). This variant is present in population databases (rs764565924, gnomAD 0.003%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and colorectal cancer (PMID: 26318770, 31992580). ClinVar contains an entry for this variant (Variation ID: 490095). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV003231537	SCV003930231	uncertain significance	not provided	2023-05-22	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 (Wang et al., 2020); Reported to co-occur with a PMS2 frameshift variant in identical twins described as having constitutional mismatch repair deficiency syndrome (CMMRD) whose tumors lacked PMS2 expression on immunohistochemistry, one of whom also lacked PMS2 expression in normal tissue; however, neither had cutaneous features of CMMRD, and familial testing results confirming phase were not reported (Bodo et al., 2015; Lavoine et al., 2015); This variant is associated with the following publications: (PMID: 26116798, 31992580, 11574484, 26318770)
All of Us Research Program, National Institutes of Health	RCV004001276	SCV004842152	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 54 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with constitutional mismatch repair deficiency syndrome and early-onset colorectal cancer (PMID: 26318770, 31992580). This variant has been identified in 4/245728 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.