ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1435C>G (p.His479Asp) (rs376344586)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197213 SCV000254598 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 479 of the PMS2 protein (p.His479Asp). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs376344586, ExAC 0.003%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 216450). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000216807 SCV000277878 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-22 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000487350 SCV000569889 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1435C>G at the cDNA level, p.His479Asp (H479D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in the Exome Sequencing Project, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Histidine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 His479Asp occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Kondo 2001, Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 His479Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000216807 SCV000903881 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001160657 SCV001322474 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Integrated Genetics/Laboratory Corporation of America RCV001192581 SCV001360810 uncertain significance not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1435C>G (p.His479Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251486 control chromosomes (gnomAD). Although, this observation needs to be cautiously considered due to the technology used does not decipher between PMS2 and the pseudogene. 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.1435C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
True Health Diagnostics RCV000216807 SCV000805282 likely benign Hereditary cancer-predisposing syndrome 2018-05-09 no assertion criteria provided clinical testing

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