Submissions for variant NM_000535.7(PMS2):c.1171G>T (p.Asp391Tyr)

dbSNP: rs1064795020

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478362	SCV000570410	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1171G>T at the cDNA level, p.Asp391Tyr (D391Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp391Tyr was not observed in approximately 6,300 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 Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Asp391Tyr occurs at a position that is not conserved and is not located in a known functional 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 Asp391Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000580849	SCV000686102	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-26	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000580849	SCV000822121	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV001238206	SCV001411005	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-16	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. 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 not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 421266). This missense change has been observed in individual(s) with hereditary cancer (PMID: 31159747). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 391 of the PMS2 protein (p.Asp391Tyr).
Ambry Genetics	RCV000580849	SCV002632146	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-25	criteria provided, single submitter	clinical testing	The p.D391Y variant (also known as c.1171G>T), located in coding exon 11 of the PMS2 gene, results from a G to T substitution at nucleotide position 1171. The aspartic acid at codon 391 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.