Submissions for variant NM_000535.7(PMS2):c.1693T>G (p.Leu565Val) (rs786202870)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165917	SCV000216672	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-07	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
GeneDx	RCV000480451	SCV000565416	uncertain significance	not provided	2014-08-01	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1693T>G at the cDNA level, p.Leu565Val (L565V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Leu565Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. PMS2 Leu565Val occurs at a position that is variable across species and is not located in a functional domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Leu565Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000531904	SCV000625552	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 565 of the PMS2 protein (p.Leu565Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415672	SCV000493781	uncertain significance	Hereditary nonpolyposis colorectal cancer type 4	2015-08-13	no assertion criteria provided	clinical testing