ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1420G>T (p.Ala474Ser) (rs373114291)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123078 SCV000166373 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 474 of the PMS2 protein (p.Ala474Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs373114291, ExAC 0.003%). This variant has been reported in the literature in an individual tested for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 135937). 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.
Ambry Genetics RCV000131575 SCV000186583 likely benign Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
GeneDx RCV000479914 SCV000565404 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1420G>T at the cDNA level, p.Ala474Ser (A474S) at the protein level, and results in the change of an Alanine to a Serine (GCA>TCA). PMS2 Ala474Ser was observed in 1/1260 individuals that underwent hereditary cancer panel testing for a history of a Lynch syndrome-associated tumor and/or polyps (Yurgelun 2015). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala474Ser 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 Ala474Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131575 SCV000686125 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-12 criteria provided, single submitter clinical testing

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