ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.883C>T (p.Arg295Trp) (rs182246929)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123094 SCV000166394 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 295 of the PMS2 protein (p.Arg295Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs182246929, ExAC 0.07%). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754, 30521064), and individuals with a personal or family history of breast cancer (PMID: 26824983, 29752822). ClinVar contains an entry for this variant (Variation ID: 135947). 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. 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 RCV000165443 SCV000216172 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence
Color RCV000165443 SCV000292179 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000487208 SCV000565973 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.883C>T at the cDNA level, p.Arg295Trp (R295W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in at least one breast cancer patient, as well as in an individual with a personal history of a Lynch syndrome associated cancer and/or colon polyps (Yurgelun 2015, Lin 2016). PMS2 Arg295Trp was observed at an allele frequency of 0.08% (16/18864) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg295Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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