Submissions for variant NM_000535.7(PMS2):c.2361C>G (p.Ile787Met)

dbSNP: rs1064794923

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481015	SCV000570222	uncertain significance	not provided	2016-05-11	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2361C>G at the cDNA level, p.Ile787Met (I787M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATC>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ile787Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. PMS2 Ile787Met occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species, and it is located within the nuclease domain (Guarne 2001, Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Ile787Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000565300	SCV000670843	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-28	criteria provided, single submitter	clinical testing	The p.I787M variant (also known as c.2361C>G), located in coding exon 14 of the PMS2 gene, results from a C to G substitution at nucleotide position 2361. The isoleucine at codon 787 is replaced by methionine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037654	SCV001201078	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 787 of the PMS2 protein (p.Ile787Met). 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 variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 421120). 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.