Submissions for variant NM_000535.7(PMS2):c.1099G>A (p.Val367Ile)

dbSNP: rs746889239

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226146	SCV000285044	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-10	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 367 of the PMS2 protein (p.Val367Ile). This variant is present in population databases (rs746889239, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 237879). 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 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.
GeneDx	RCV000481764	SCV000572664	uncertain significance	not provided	2017-08-11	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1099G>A at the cDNA level, p.Val367Ile (V367I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val367Ile was observed at an allele frequency of 0.03% (5/16510) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Val367Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain. 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 Val367Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000569779	SCV000663513	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-04	criteria provided, single submitter	clinical testing	The p.V367I variant (also known as c.1099G>A), located in coding exon 10 of the PMS2 gene, results from a G to A substitution at nucleotide position 1099. The valine at codon 367 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was reported in an Asian patient undergoing multigene panel testing; this individual was diagnosed with breast cancer at age 49, had no reported family history of cancer, and also had another PMS2 gene alteration, c.1688_1689delGAinsAG (p.Arg563Gln) (Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660). This amino acid position is not well 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481764	SCV000889604	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569779	SCV000911235	likely benign	Hereditary cancer-predisposing syndrome	2016-10-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001162267	SCV001324214	uncertain significance	Lynch syndrome 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479070	SCV004222811	uncertain significance	not specified	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1099G>A (p.Val367Ile) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251260 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Lynch Syndrome (4.4e-05 vs 0.00011), allowing no conclusion about variant significance. c.1099G>A has been reported in the literature as a VUS in settings of multigene panel testing for individuals affected with multiple primary cancers (example, Chan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30093976). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (LB, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998785	SCV004839848	likely benign	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing