Submissions for variant NM_000535.7(PMS2):c.1439G>C (p.Gly480Ala)

dbSNP: rs373917897

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214480	SCV000274497	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	clinical testing	The p.G480A variant (also known as c.1439G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1439. The glycine at codon 480 is replaced by alanine, an amino acid with similar properties. 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.
Invitae	RCV000233535	SCV000285069	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 480 of the PMS2 protein (p.Gly480Ala). This variant is present in population databases (rs373917897, gnomAD 0.0009%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 230824). 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.
GeneDx	RCV000485778	SCV000565406	uncertain significance	not provided	2023-06-08	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; Observed in an individual with pancreatic cancer (Grant et al., 2015); This variant is associated with the following publications: (PMID: 25479140)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485778	SCV000888392	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214480	SCV000912093	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 480 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 an individual affected with pancreatic cancer (PMID: 25479140). This variant has been identified in 1/251490 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532968	SCV001748792	uncertain significance	not specified	2021-07-03	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1439G>C (p.Gly480Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1439G>C has been reported in the literature among rare non synonymous single nucleotide variants (SNV) identified in a cohort of patients with pancreatic cancer (Grant_2015). This report does 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.