ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.881G>A (p.Arg294Gln) (rs373239341)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222705 SCV000277568 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence
Invitae RCV000473195 SCV000551977 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 294 of the PMS2 protein (p.Arg294Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs373239341, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 233232). 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 glutamine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000486648 SCV000569365 uncertain significance not provided 2017-10-07 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.881G>A at the cDNA level, p.Arg294Gln (R294Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a small cell lung cancer (Jiang 2016). PMS2 Arg294Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Arg294Gln occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Arg294Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000662988 SCV000785977 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-29 criteria provided, single submitter clinical testing
Mendelics RCV000708991 SCV000838187 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000222705 SCV000903867 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing
Mendelics RCV000662988 SCV001137312 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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