ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2012C>T (p.Thr671Met) (rs587780046)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000488189 SCV000149579 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2012C>T at the cDNA level, p.Thr671Met (T671M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been observed in individuals with pancreatic, breast, or colorectal cancer, of whom one individual had a mismatch repair proficient and microsatellite stable colon cancer (Tung 2015, Hu 2016, Yang 2016, Yurgelun 2017, Goidescu 2018). 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 (Lek 2016). PMS2 Thr671Met is located within 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 evidence, it is unclear whether PMS2 Thr671Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115670 SCV000186832 benign Hereditary cancer-predisposing syndrome 2015-09-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000200451 SCV000255287 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 671 of the PMS2 protein (p.Thr671Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. The frequency data for this variant in the population databases (rs587780046, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals affected with pancreatic cancer and colorectal cancer (PMID: 27449771, 26483394, 28135145). ClinVar contains an entry for this variant (Variation ID: 127770). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488189 SCV000575508 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000488189 SCV000601835 uncertain significance not provided 2019-04-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515168 SCV000611421 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212865 SCV000697320 uncertain significance not specified 2019-08-23 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2012C>T (p.Thr671Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 168512 control chromosomes (gnomAD). The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. However, this observance needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. The variant, c.2012C>T, has been reported in the literature in individuals affected with breast cancer, colorectal cancer or pancreatic cancer (Hu 2015, Tung 2014, Yang 2016, Yurgelun 2017, Goidescu 2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one of these patients, co-occurrence with another pathogenic variant has been reported (KRAS c.34G>T, p.Gly12Cys, Yurgelun_2017), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant predominantly as uncertain significance and once benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneKor MSA RCV000115670 SCV000822126 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000708981 SCV000838173 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000987820 SCV001137284 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144642 SCV000189969 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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