Submissions for variant NM_000535.7(PMS2):c.2367G>A (p.Met789Ile)

dbSNP: rs766565506

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561492	SCV000663503	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The p.M789I variant (also known as c.2367G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2367. The methionine at codon 789 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706959	SCV000836034	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 789 of the PMS2 protein (p.Met789Ile). 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 Lynch syndrome-related cancer (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 480330). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284326	SCV001470053	uncertain significance	not provided	2019-09-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001284326	SCV001772960	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with a Lynch-syndrome related cancer (PMID: 31391288); This variant is associated with the following publications: (PMID: 31391288, 22949387, Fukui2011[Chapter])
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584373	SCV001821253	uncertain significance	not specified	2025-01-06	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2367G>A (p.Met789Ile) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2367G>A has been reported in the literature in an individual affected with cancer, without strong evidence for causality (Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 480330). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000561492	SCV004359001	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 789 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 reported for this variant. This variant has been reported in an individual with unspecified cancer (PMID: 31391288). This variant has not been identified 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.