ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1918G>A (p.Glu640Lys) (rs886062400)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000278327 SCV000469724 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.
GeneDx RCV000482265 SCV000565419 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1918G>A at the cDNA level, p.Glu640Lys (E640K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a lung tumor (Shi 2016). PMS2 Glu640Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Glu640Lys is located in the MLH1 interaction domain (Kondo 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether PMS2 Glu640Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000543398 SCV000625565 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 640 of the PMS2 protein (p.Glu640Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 360542). 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 lysine 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 RCV000562926 SCV000670857 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000562926 SCV000904157 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-14 criteria provided, single submitter clinical testing
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093664 SCV001250845 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing

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