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 2020-10-30 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);Other data supporting benign classification;Structural Evidence
GeneDx RCV000587309 SCV000279141 uncertain significance not provided 2021-02-25 criteria provided, single submitter clinical testing Observed in individuals with colon cancer (Chubb 2015, Haraldsdottir 2017); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25559809, 28466842)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000213296 SCV000903147 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-11 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer with tumor showing microsatellite stability (PMID: 25559809). A case-control study did not produce conclusive evidence for the association of this variant with colorectal cancer (PMID: 28466842). This variant has been identified in 5/251300 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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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