Submissions for variant NM_000535.7(PMS2):c.727G>T (p.Val243Phe)

dbSNP: rs867655834

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479913	SCV000566970	uncertain significance	not provided	2016-12-15	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.727G>T at the cDNA level, p.Val243Phe (V243F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val243Phe 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 Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Val243Phe occurs at a position that is conserved in mammals and is located in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Val243Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758685	SCV000887457	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	PMS2 NM_000535.5:c.727G>T has a 16.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Invitae	RCV001054961	SCV001219323	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-09-21	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 419274). This missense change has been observed in individual(s) with breast cancer (PMID: 29752822). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 243 of the PMS2 protein (p.Val243Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine.
Color Diagnostics, LLC DBA Color Health	RCV001187833	SCV001354720	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001187833	SCV002669203	uncertain significance	Hereditary cancer-predisposing syndrome	2017-06-12	criteria provided, single submitter	clinical testing	The p.V243F variant (also known as c.727G>T), located in coding exon 7 of the PMS2 gene, results from a G to T substitution at nucleotide position 727. The valine at codon 243 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly 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.