ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1329A>T (p.Arg443Ser) (rs192720342)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223294 SCV000279935 uncertain significance not provided 2016-02-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1329A>T at the cDNA level, p.Arg443Ser (R443S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in 1000 Genomes, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Arg443Ser occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant may create a new cryptic splice donor site upstream of the natural splice donor site of intron 11 and lead to abnormal splicing. 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 Arg443Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570228 SCV000676166 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-22 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000630221 SCV000751177 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 443 of the PMS2 protein (p.Arg443Ser). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs192720342, ExAC 0.009%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234869). 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 serine 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.
Color RCV000570228 SCV000904174 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255534 SCV001431996 uncertain significance not specified 2020-08-13 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1329A>T (p.Arg443Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251440 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.1329A>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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