ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1344A>T (p.Gly448=) (rs759192470)

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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 RCV000164596 SCV000215255 likely benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing
Color RCV000164596 SCV000911287 likely benign Hereditary cancer-predisposing syndrome 2017-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000442013 SCV000517396 likely benign not specified 2016-12-14 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 RCV000442013 SCV000920043 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1344A>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246256 control chromosomes. 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.1344A>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, with one laboratory classifying the variant as uncertain significance and the other as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000229726 SCV000285065 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change affects codon 448 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. This variant is present in population databases (rs759192470, ExAC 0.001%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 185217). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare silent change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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