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

gnomAD frequency: 0.00016  dbSNP: rs201343342

Total submissions: 18

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	2024-01-31	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Diagnostics, LLC DBA Color Health	RCV000115698	SCV000537589	likely benign	Hereditary cancer-predisposing syndrome	2019-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212836	SCV000601852	benign	not specified	2021-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515284	SCV000611425	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 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	2023-09-14	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 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 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly 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_2010). It was also reported in patients with endometrial, kidney, breast and colorectal cancer, without strong evidence for causality (example, Lu_2015, Tung_2015, Tung_2016, Yurgelun_2017, Krivokuca_2021, Guindalini_2022). This variant has also been reported in an unaffected sibling and a proband in compound heterozygosity with a pathogenic exon 5 to 12 deletion (Shuen_2019). Both siblings demonstrated absent staining of PMS2 on non-neoplastic tissue. In addition, a recent large scale case-control study of breast cancer reported this variant in 13/53461 controls and 8/60466 cases (Dorling_2021). At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.2808_2811del, p.Ala938Profs*21; Tung_2016), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Shuen_2019). The most pronounced variant effect results in approximately 21% mismatch repair (MMR) activity. The authors suggested that an MMR activity of 10% to 20% may represent an intermediate phenotype between classic CMMRD and Lynch syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 27060170, 35264596, 22703879, 34284872, 26689913, 30608896, 25186627, 26976419, 20205264, 28135145, 30447919, 33471991). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=8; Likely benign, n=3; Benign, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000123089	SCV000838200	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001159382	SCV001321092	uncertain significance	Lynch syndrome 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	Lynch syndrome 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].
Genetic Services Laboratory, University of Chicago	RCV000212836	SCV002069435	uncertain significance	not specified	2020-02-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.53T>C, in exon 2 that results in an amino acid change, p.Ile18Thr. This sequence change has been described in the gnomAD database with a low population frequency of 0.03% in the overall population and a relatively high population frequency of 0.72% in the Ashkenazi Jewish population (dbSNP rs201343342). This sequence change was identified in a patient with colorectal cancer whose tumor exhibited isolated loss of PMS2 expression by IHC (Vaughn et al., 2010). The p.Ile18Thr change was identified in an Ashkenazi Jewish breast cancer patient who was also found to have a pathogenic sequence change in BRCA2 (Tung et al., 2016). The p.Ile18Thr change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Ile18Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile18Thr change remains unknown at this time.
Sema4, Sema4	RCV000115698	SCV002530357	likely benign	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149612	SCV003837743	uncertain significance	Breast and/or ovarian cancer	2023-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212836	SCV004243291	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944883	SCV004761559	likely benign	PMS2-related disorder	2019-12-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.