ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2405G>A (p.Arg802Gln) (rs1060503143)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464576 SCV000552042 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 802 of the PMS2 protein (p.Arg802Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 411071). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000708978 SCV000838167 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192583 SCV001360814 uncertain significance not specified 2019-07-22 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2405G>A (p.Arg802Gln) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-06 in 224314 control chromosomes (gnomAD). 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.2405G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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