Submissions for variant NM_000535.7(PMS2):c.2212G>T (p.Val738Phe)

dbSNP: rs758225108

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000662652	SCV000785339	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
Invitae	RCV001244703	SCV001417945	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 738 of the PMS2 protein (p.Val738Phe). 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: 548763). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797773	SCV002041594	likely benign	not specified	2021-11-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255499	SCV002530274	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662652	SCV004019750	uncertain significance	Lynch syndrome 4	2023-04-03	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000662652	SCV004048512	uncertain significance	Lynch syndrome 4		criteria provided, single submitter	clinical testing	The missense variant in c.2212G>T (p.Val738Phe) in PMS2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val738Phe variant is reported with the allele frequency of 0.03344% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as conflicting - uncertain significance/ likely benign. The amino acid Val at position 738 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is variable across species. For these reasons, this variant has been classified as Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV002255499	SCV004359031	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with phenylalanine at codon 738 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. In a large breast cancer case-control study, this variant was reported in one individual affected with breast cancer and one unaffected individual (PMID: 33471991). This variant has been identified in 83/248174 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequence in the PMS2CL pseudogene. 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.