Submissions for variant NM_000535.7(PMS2):c.1354G>A (p.Gly452Ser) (rs569947936)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221391	SCV000274496	likely benign	Hereditary cancer-predisposing syndrome	2018-08-21	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx	RCV000521141	SCV000616825	uncertain significance	not provided	2017-11-03	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1354G>A at the cDNA level, p.Gly452Ser (G452S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gly452Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly452Ser 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 Gly452Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000629994	SCV000750950	uncertain significance	Hereditary nonpolyposis colon cancer	2019-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 452 of the PMS2 protein (p.Gly452Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs569947936, ExAC 0.02%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 230823). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color	RCV000221391	SCV000903598	likely benign	Hereditary cancer-predisposing syndrome	2017-01-03	criteria provided, single submitter	clinical testing

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