ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1439G>C (p.Gly480Ala) (rs373917897)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214480 SCV000274497 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000233535 SCV000285069 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 480 of the PMS2 protein (p.Gly480Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 230824). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 2017-06-30 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1439G>C at the cDNA level, p.Gly480Ala (G480A) at the protein level, and results in the change of a Glycine to an Alanine (GGA>GCA). This variant was reported in at least one individual with pancreatic cancer (Grant 2015). PMS2 Gly480Ala was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. PMS2 Gly480Ala occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Gly480Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485778 SCV000888392 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing
Color RCV000214480 SCV000912093 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing

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