Submissions for variant NM_000535.7(PMS2):c.994G>A (p.Val332Ile)

gnomAD frequency: 0.00001  dbSNP: rs1236095389

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000545777	SCV000625717	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 332 of the PMS2 protein (p.Val332Ile). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer (PMID: 28135145, 35449176). ClinVar contains an entry for this variant (Variation ID: 455754). 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	RCV000590366	SCV000697406	uncertain significance	not provided	2017-03-16	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.994G>A (p.Val332Ile) variant located in the Ribosomal protein S5 domain 2-type fold (via Interpro) causes a missense change involving the alteration of a conserved nucleotide and 4/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant is absent in 113932 control chromosomes (ExAC, 1000 Gs, or ESP). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758684	SCV000887456	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	PMS2 NM_000535.5:c.994G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 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.
Color Diagnostics, LLC DBA Color Health	RCV000775689	SCV000910100	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 332 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. This variant has been reported in one individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 5/249848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV000775689	SCV001181360	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	The p.V332I variant (also known as c.994G>A), located in coding exon 10 of the PMS2 gene, results from a G to A substitution at nucleotide position 994. The valine at codon 332 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been previously reported in an individual diagnosed with colorectal cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). This amino acid position is 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590366	SCV001469608	uncertain significance	not provided	2019-10-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000590366	SCV001783798	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 11574484, 28135145)