ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1231_1232delinsTT (p.Glu411Leu) (rs786202871)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165918 SCV000216673 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000481458 SCV000571404 uncertain significance not specified 2016-08-18 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1231_1232delGAinsTT at the cDNA level and p.Glu411Leu (E411L) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets is AGAA[delGA][insTT]AAAAAAAG. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Glutamic acid to a Leucine (GAA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither PMS2 c.1231_1232delGAinsTT nor Glu411Leu (by this or an alternate nucleotide change) was observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic acid and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu411Leu occurs at a position that is not conserved and is not located in a known functional domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Glu411Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000694340 SCV000822780 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with leucine at codon 411 of the PMS2 protein (p.Glu411Leu). The glutamic acid residue is moderately conserved and there is a large physicochemical difference between glutamate and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186339). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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