ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1864A>G (p.Met622Val) (rs370853512)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221658 SCV000273417 likely benign Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Color RCV000221658 SCV000910813 likely benign Hereditary cancer-predisposing syndrome 2017-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000588546 SCV000566510 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1864A>G at the cDNA level and p.Met622Val (M622V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported in at least one individual with a Lynch-associated cancer and/or polyps and in two siblings with childhood gliosarcomas (Plon 2011, Yurgelun 2015). The two siblings were also identified as having a PMS2 nonsense variant, although it was not specified whether PMS2 Met622Val and the nonsense variant were on the same allele (in cis) or opposite alleles (in trans) (Plon 2011). In addition, this variant was shown to reduce PMS2 binding to MLH1 in mammalian cells (Plon 2011). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Met622Val is located in the MLH1 interaction domain (Kondo 2001). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether PMS2 Met622Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588546 SCV000697316 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1864A>G (p.Met622Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the ExAC database in 46/121374 control chromosomes at a frequency of 0.000379, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), however ExAC does not use technology that is able to differentiate between PMS2 and highly homologous psuedogenes, therefore pseudogene intereference cannot be ruled out. The variant has been reported in affected individuals in the literature, without strong evidence for causality. A functional study suggests the binding of PMS2-M622V to MLH1 was consistently decreased, however quantification was not provided (Plon_2011). The variant was classified by one reputable clinical lab as a VUS, and by another as likely benign. Taken together, until additional functional and clinical data becomes available, this variant is classified as VUS.
Invitae RCV000205706 SCV000261560 likely benign Hereditary nonpolyposis colon cancer 2017-11-16 criteria provided, single submitter clinical testing

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