ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.319C>T (p.Arg107Trp) (rs188006077)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586637 SCV000149602 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.319C>T at the cDNA level, p.Arg107Trp (R107W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed individuals with suspected Lynch syndrome and in an individual with suspected constitutional mismatch repair deficiency syndrome (Suerink 2015, ten Broeke 2015, van der Klift 2016). Splicing assays performed using minigene and RT-PCR approaches identified alternate transcripts in addition to the wild type transcript; however, these were not quantified (van der Klift 2015). In addition, an in vitro mismatch repair assay showed deficient activity (van der Klift 2016). PMS2 Arg107Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in motif III of 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 Arg107Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115693 SCV000187425 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-09 criteria provided, single submitter clinical testing The p.R107W variant (also known as c.319C>T), located in coding exon 4 of the PMS2 gene, results from a C to T substitution at nucleotide position 319. The arginine at codon 107 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in trans with a PMS2 exon 10 deletion in a patient with suspected CMMRD; however, PMS2 protein expression was normal by immunohistochemistry (IHC) performed on the patient's tumor sample (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). This alteration has also been identified in several individuals whose family history met Amsterdam II criteria for Lynch syndrome and/or colorectal tumors showed normal PMS2 protein expression on IHC, but displayed high microsatellite instability (MSI-H) (Ambry internal data; van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). In an in vitro mismatch repair (MMR) complementation assay, the MMR activity of p.R107W was reduced to less than 20% compared to wild type (100%), which was similar to other pathogenic/likely pathogenic variants in the assay (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). Patient RNA analysis and in vitro minigene assays of the c.319C>T variant both demonstrated expression of alternatively spliced transcripts in addition to the full length PMS2 transcript, but this was not directly quantified (van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000465201 SCV000552039 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 107 of the PMS2 protein (p.Arg107Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs188006077, ExAC 0.01%). This variant has been reported in a family with suspected Lynch syndrome (PMID: 25512458, 26110232), and in trans with a pathogenic variant in an individual with suspected constitutional mismatch repair deficiency syndrome (PMID: 27435373). ClinVar contains an entry for this variant (Variation ID: 127789) Experimental studies have shown that this missense change results in a minor upregulation of PMS2 alternative transcripts in vitro and in RNA isolated from individuals with Lynch syndrome. However, no quantification of the exact differences in the rate of expression of these transcripts was provided (PMID: 26247049). It has also been shown to disrupt PMS2 mismatch repair activity in vitro (PMID: 27435373). 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 Health, Inc RCV000115693 SCV000686190 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586637 SCV000806214 uncertain significance not provided 2016-11-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174801 SCV001338147 uncertain significance not specified 2020-02-10 criteria provided, single submitter clinical testing Variant summary: PMS2 c.319C>T (p.Arg107Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Although the c.319C>T falls within exon 4, and 4/4 programs in Alamut predict that this variant does not affect normal splicing, splicing studies have shown that this variant promotes the expression of the alternative transcripts lacking exon 4 over full-length (FL) transcripts (van der Klift_2015). The alternative transcripts are also found in wt RNA, and, since the exact differences in the rate of expression of the FL and alternative transcripts could not be determined, the translational impact of this variant remains uncertain. The variant allele was found at a frequency of 1.3e-05 in 236786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.319C>T has been reported in the literature in individuals affected with or with a family history of Lynch Syndrome-spectrum cancers, as well as in at least one patient with suspected CMMRD who carried a second pathogenic variant (van der Klift_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one patient with endometrial cancer, co-occurrence with another pathogenic variant was reported (POLE, p.R563*), providing supporting evidence for a benign role (Stelloo_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

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