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 2019-09-11 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification
Invitae RCV000465201 SCV000552039 uncertain significance Hereditary nonpolyposis colon cancer 2019-07-13 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 RCV000115693 SCV000686190 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586637 SCV000697358 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The c.319C>T (p.Arg107Trp) in PMS2 gene is a missense variant involves a highly conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant is located within DNA mismatch repair protein MutL domain. Although the c.319C>T falls within exon 4, and 5/5 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 exon4 over full-length (FL) transcripts. The alternative transcripts are also being found in the 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 is present in the control population dataset of ExAC at a frequency of 8.798e-06 (1/113660 chrs tested), which does not exceed the maximal expected allele frequency for a non-common pathogenic variant (0.00011). The variant has been reported in at least 3 affected individuals presented with CRC, endometrial cancer (EnCa) and in patient with suspected CMMRD, respectively (Suerink, 2015; van der Klift, 2016, Stelloo, 2017). In at least 2 patients another alteration of PMS gene were reported, and only one patient had presented with suspected, but not definitively confirmed dx of CMMRD (van der Klift, 2016, Stelloo, 2017). Both reports allow to speculate that c.319C>T may not be a primary cause of the clinical presentations in these patients. In addition, the variant of interest has been reported as VUS by a reputable database/clinical laboratory. Taken all together, the variant was classified as VUS, until more data becomes available.
PreventionGenetics,PreventionGenetics RCV000586637 SCV000806214 uncertain significance not provided 2016-11-30 criteria provided, single submitter clinical testing

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