ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.452G>A (p.Arg151His) (rs35629870)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766584 SCV000211589 uncertain significance not provided 2016-09-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.452G>A at the cDNA level, p.Arg151His (R151H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in an individual with colon cancer and who met criteria for Lynch syndrome testing (Sheng 2010). PMS2 Arg151His was not observed at significant allele frequency in 1000 Genomes. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. PMS2 Arg151His occurs at a position that is conserved across species and is located in the ATPase domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Arg151His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000456758 SCV000551995 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 151 of the PMS2 protein (p.Arg151His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs35629870, ExAC 0.01%). This variant has been observed in individuals affected with Lynch syndrome (PMID: 20698049), as well as in an individual with a high risk of breast cancer (PMID: 29752822). ClinVar contains an entry for this variant (Variation ID: 156510). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160896 SCV000601850 uncertain significance not specified 2017-02-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561546 SCV000670802 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-27 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000561546 SCV000903602 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-04 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144643 SCV000189970 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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