ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1552G>A (p.Glu518Lys) (rs376142390)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206422 SCV000259586 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 518 of the PMS2 protein (p.Glu518Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs376142390, ExAC 0.003%). This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 28466842). ClinVar contains an entry for this variant (Variation ID: 219612). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000213296 SCV000273555 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Structural Evidence;Other data supporting benign classification
GeneDx RCV000587309 SCV000279141 uncertain significance not provided 2017-05-24 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1552G>A at the cDNA level, p.Glu518Lys (E518K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant was observed in one individual with microsatellite stable colorectal cancer who had a family history of early onset colorectal cancer (Chubb 2015). 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 (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu518Lys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Glu518Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587309 SCV000697301 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1552G>A (p.Glu518Lys) variant involves the alteration of a non-conserved nucleotide and is present outside of the known functional domains. 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 2/120582 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). This variant was observed in one patient with early onset colorectal cancer who had a family history of colorectal cancer and her tumor showed stable microsatellite (Chubb 2015). Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Fulgent Genetics,Fulgent Genetics RCV000765957 SCV000897378 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000213296 SCV000903147 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587309 SCV001134581 uncertain significance not provided 2019-03-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001160656 SCV001322471 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.

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