ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.255G>A (p.Leu85=) (rs200491279)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160903 SCV000212742 likely benign Hereditary cancer-predisposing syndrome 2014-07-23 criteria provided, single submitter clinical testing
Color RCV000160903 SCV000537436 likely benign Hereditary cancer-predisposing syndrome 2015-04-02 criteria provided, single submitter clinical testing
Counsyl RCV000662801 SCV000785621 likely benign Hereditary nonpolyposis colorectal cancer type 4 2017-10-16 criteria provided, single submitter clinical testing
GeneDx RCV000212839 SCV000211598 benign not specified 2014-08-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000587054 SCV000697355 uncertain significance not provided 2016-09-07 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.255G>A (p.Leu85Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 25/114936 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003681 (23/62476). This frequency is about 3.25 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, the sequencing technology utalized by ExAC cannot rule out the possibility of pseudogene overlap, therefore this frequency data cannot be used as support for the benign impact of this variant (it is located in a region of the gene with only one mismatch 25 bp up/downstream compared to the pseudogene). A conference abstract cites the variant of interest in one individual with PMS2 protein loss in her tumor, and this patient was shown to have a splicing defect whereby 50% exon 4 skipping was observed (the variant is located at the 5th nucleotide in exon 4). Multiple clinical diagnostic laboratories have classified this variant as benign/likley benign, without evidence to independently evaluate. Due to the possibility of an impact on splicing, and unreliable control population data, this variant has been classified as a VUS.
Invitae RCV000197796 SCV000253299 likely benign Hereditary nonpolyposis colon cancer 2017-12-27 criteria provided, single submitter clinical testing
PreventionGenetics RCV000587054 SCV000806211 likely benign not provided 2017-04-03 criteria provided, single submitter clinical testing

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