ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.320G>A (p.Arg107Gln) (rs63751284)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524469 SCV000166384 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 107 of the PMS2 protein (p.Arg107Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63751284, ExAC 0.02%). This variant has been reported in an individual affected with Lynch syndrome (PMID: 14756672). However, an additional publication questions these results due to the high degree of similarity between PMS2 and its pseudogene (PMID: 15521988). ClinVar contains an entry for this variant (Variation ID: 91351) 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 disruptive, but 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.
Ambry Genetics RCV000216503 SCV000273049 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000216578 SCV000279228 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.320G>A at the cDNA level, p.Arg107Gln (R107Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been reported in an individual suspected of having Lynch syndrome as well as in an individual with colorectal cancer (Thompson 2004, Yurgelun 2017). PMS2 Arg107Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATP binding motif III and ATP lid regions within the ATPase domain (Guarne 2001). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may create a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether PMS2 Arg107Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000216503 SCV000686191 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216578 SCV000888413 uncertain significance not provided 2019-05-08 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030725 SCV001193693 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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