Submissions for variant NM_000535.7(PMS2):c.2062A>G (p.Ile688Val)

gnomAD frequency: 0.00001  dbSNP: rs1060503144

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467081	SCV000552048	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-21	criteria provided, single submitter	clinical testing	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 sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 688 of the PMS2 protein (p.Ile688Val). 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: 411074). 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.
Ambry Genetics	RCV000562935	SCV000670771	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-17	criteria provided, single submitter	clinical testing	The p.I688V variant (also known as c.2062A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2062. The isoleucine at codon 688 is replaced by valine, an amino acid with highly similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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.
Counsyl	RCV000662654	SCV000785341	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000662654	SCV001137283	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800682	SCV002046596	uncertain significance	not provided	2021-02-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562935	SCV002530255	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
GeneDx	RCV001800682	SCV003927451	uncertain significance	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV000662654	SCV004019752	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.
PreventionGenetics, part of Exact Sciences	RCV003418198	SCV004106201	uncertain significance	PMS2-related condition	2023-09-08	criteria provided, single submitter	clinical testing	The PMS2 c.2062A>G variant is predicted to result in the amino acid substitution p.Ile688Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6022567-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411074/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.