Submissions for variant NM_000535.7(PMS2):c.2T>A (p.Met1Lys)

dbSNP: rs587780059

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212834	SCV000211587	pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Described as a pathogenic founder variant in the Icelandic population (Haraldsdottir et al., 2017); Identified in the heterozygous state in an individual with a personal and family history of colorectal cancer (Chubb et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 27742654, 30787465, 31447099, 28466842, 25559809, 27476653, 29922827, 32719484, 33087929, 30764633)
Ambry Genetics	RCV000160895	SCV000214325	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the PMS2 gene. This variant results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This alteration was previously identified in a patient with colon cancer and in a patient with CMMRD who had another PMS2 mutation in trans (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Adam R et al. Am. J. Hum. Genet. 2016 Aug;99(2):337-51). Other alterations impacting the PMS2 initiation codon have been reported in individuals with early-onset, Lynch syndrome-associated malignancies and tumors demonstrating isolated loss of PMS2 staining by immunohistochemistry (IHC) (Senter et al. Gastroenterology. 2008 Aug;135(2):419-28; Borràs E et al. J. Med. Genet. 2013 Aug; 50(8):552-63). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Genetic Services Laboratory, University of Chicago	RCV000500749	SCV000596477	pathogenic	Lynch syndrome 4	2016-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160895	SCV000691064	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon of the PMS2 gene. Although functional studies have not been reported for this variant, it is expected to disrupt the expression of the full-length PMS2 protein. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 26681312) and in individuals affected with constitutional mismatch-repair deficiency who carried another pathogenic variant in PMS2 (PMID: 27476653, 30764633). This variant has been identified in 2/250260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions affecting the same start codon are considered to be disease-causing (ClinVar variation ID: 91323, 127788, 142777, 231873, 957082, 450786, 820477), suggesting that this start codon is critical for PMS2 translation. Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000500749	SCV000785677	pathogenic	Lynch syndrome 4	2017-10-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763593	SCV000894432	pathogenic	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781734	SCV000920019	pathogenic	Hereditary nonpolyposis colon cancer	2020-11-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250260 control chromosomes (gnomAD). c.2T>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Chubb_2015, Susswein_2016). It has also been reported in compound heterozygous individuals affected with Constitutional Mismatch Repair-Deficiency syndrome with evidence of complete loss of PMS2 in both tumor and normal tissue following immunohistochemical staining (e.g. Adam_2016, Pavelka_2019). These data indicate that the variant is likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Other variants affecting the PMS2 initiation codon (e.g. c.1A>G, c.1A>T, c.2T>C) have been reported as disease-associated indicating the functional importance of this position. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000500749	SCV001429095	uncertain significance	Lynch syndrome 4	2018-05-16	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000500749	SCV002579149	likely pathogenic	Lynch syndrome 4	2022-05-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212834	SCV002774370	pathogenic	not provided	2021-06-18	criteria provided, single submitter	clinical testing	This variant is located in the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The variant has been reported in affected individuals with colorectal cancer in the published literature (PMIDs: 25559809 (2015) and 26681312 (2015)). This variant has also been reported in individuals with constitutional mismatch repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMIDs: 27476653 (2016) and 30764633 (2018)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000212834	SCV003818401	pathogenic	not provided	2022-08-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000500749	SCV004019807	pathogenic	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30680046, 27476653, 18602922].
PreventionGenetics, part of Exact Sciences	RCV003407599	SCV004108717	pathogenic	PMS2-related condition	2023-02-10	criteria provided, single submitter	clinical testing	The PMS2 c.2T>A variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in the heterozygous state in patients with colorectal cancer (see for example Chubb et al. 2015. PubMed ID: 25559809; Susswein et al. 2016. PubMed ID: 26681312). This variant has also been reported in the compound heterozygous state in association with constitutional mismatch repair cancer syndrome (Adam et al. 2016. PubMed ID: 27476653). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6048649-A-T), and it is classified by the majority of submitters to ClinVar as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/182809/). This variant is interpreted as pathogenic.
deCODE genetics, Amgen	RCV000500749	SCV004022255	pathogenic	Lynch syndrome 4	2023-07-21	no assertion criteria provided	research	The variant NM_000535.7:c.2T>A (chr7:6009018) in PMS2 was detected in 51 heterozygotes out of 58K WGS Icelanders (MAF= 0,044%). Following imputation in a set of 166K Icelanders (144 imputed heterozygotes) we observed an association with colorectal cancer using 4991 cases and 314812 controls (OR= 2.25, P= 4.86e-02). This variant has been reported in ClinVar previously as pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PVS1, PS4) this variant classifies as pathogenic.