ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.53T>C (p.Ile18Thr) (rs201343342)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212836 SCV000149607 uncertain significance not specified 2017-03-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.53T>C at the cDNA level, p.Ile18Thr (I18T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant was observed in at least one individual undergoing genetic testing for Lynch syndrome with a tumor that exhibited isolated loss of PMS2 by immunohistochemistry (Vaughn 2010). This variant was also reported in a patient with endometrial cancer, another with renal cancer, one with breast cancer who also carried a pathogenic variant in BRCA2 and in 2/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012, Lu 2015, Tung 2016). PMS2 Ile18Thr was not observed in approximately 3,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile18Thr occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Ile18Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001083711 SCV000166389 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115698 SCV000187410 likely benign Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;No disease association in appropriately sized case-control study(ies)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000123089 SCV000296937 uncertain significance Lynch syndrome 2015-07-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115698 SCV000537589 likely benign Hereditary cancer-predisposing syndrome 2019-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034630 SCV000601852 likely benign not provided 2019-06-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515284 SCV000611425 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212836 SCV000697372 uncertain significance not specified 2019-09-12 criteria provided, single submitter clinical testing Variant summary: PMS2 c.53T>C (p.Ile18Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 245578 control chromosomes. The observed variant frequency is approximately 3-folds over the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), suggesting that the variant is benign. However, the variant is located in a PMS2 region that shows high homology to pseudogenes, therefore this frequency data should be taken with caution. c.53T>C has been observed in a Lynch Syndrome patient with no other pathogenic mutations and with tumors that exhibited isolated loss of PMS2 expression by IHC (Vaughn_PMS2_HM_2010). It was also reported in patients with endometrial, kidney, breast and colorectal cancer, without strong evidence for causality (Lu_2015, Tung_2015, Tung_2016, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811del, p.Ala938Profs*21; Tung_2016), 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 six times as uncertain significance and twice as likely benign/benign. Based on the evidence outlined above, the variant was classified as VUS.
Mendelics RCV000123089 SCV000838200 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001159382 SCV001321092 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001159382 SCV001526100 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-03-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034630 SCV000043440 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000034630 SCV001553682 likely benign not provided no assertion criteria provided clinical testing The PMS2 p.Ile18Thr variant was identified in 6 of 2462 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, hemophilia A, and atherosclerosis (Gorski 2016, Tung 20016, Vaughn 2010, Johnston 2012). The variant was also identified in dbSNP (ID: rs201343342 as “with uncertain significance allele”), and ClinVar (6x as uncertain significance by GeneDx, Children's Hospital of Philadelphia, Color Genomics, Quest Diagnostics, Fulgent Genetics and NIH; 1x as likely benign by Ambry Genetics; and 1x as benign by Invitae) and the Insight Hereditary Tumors Database (1x as effect unknown). The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang Colon Cancer, or the Mismatch Repair Genes Variant database. The variant was identified in control databases in 88 of 271252 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Other in 1 of 6380 chromosomes (freq: 0.0002), European Non-Finnish in 13 of 122684 chromosomes (freq: 0.0001), and Ashkenazi Jewish in 74 of 9990 chromosomes (freq: 0.007); it was not observed in the African, Latino, East Asian, European Finnish, or South Asian populations. The p.Ile18Thr residue is conserved across mammals and other organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in this laboratory with a co-occurring, pathogenic MSH6 variant (c.3840_3846del, p.Glu1281Leufs*44), increasing the likelihood that the p.Ile18Thr variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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