ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1432A>G (p.Ser478Gly) (rs144389038)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166020 SCV000216779 likely benign Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Invitae RCV000200794 SCV000254597 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 478 of the PMS2 protein (p.Ser478Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs144389038, 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: 186428). 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 glycine 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.
GeneDx RCV000423126 SCV000518450 likely benign not specified 2017-08-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000166020 SCV000909654 likely benign Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000423126 SCV000920049 uncertain significance not specified 2018-06-15 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1432A>G (p.Ser478Gly) 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 1.6e-05 in 121410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1432A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 likely benign, 2 VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000987830 SCV001137299 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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