Submissions for variant NM_000535.7(PMS2):c.1A>T (p.Met1Leu)

dbSNP: rs587779333

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132181	SCV000187260	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-07	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the PMS2 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome (Yurgelun MB et al. Gastroenterology 2015 Sep;149(3):604-13.e20) and in a cohort of Chinese breast cancer patients (Li JY et al. Int J Cancer 2019 01;144(2):281-289). This specific alteration has been reported in conjunction with PMS2 pathogenic mutations in individuals with constitutional mismatch repair deficiency (CMMR-D) phenotypes, although phase of the alterations was unknown (Adam R et al. Am J Hum Genet 2016 Aug;99(2):337-51; Ambry internal data). A similar alteration impacting the same nucleotide position (c.1A>G) has been reported in trans with a second pathogenic PMS2 mutation in three patients with CMMR-D who had absence of PMS2 staining observed in both tumor and normal tissues (Senter L et al. Gastroenterology 2008 Aug;135(2):419-28) and in an individual diagnosed with early-onset endometrial cancer demonstrating isolated loss of PMS2 by IHC analysis (Borràs E et al. J. Med. Genet. 2013 Aug;50:552-63). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000218553	SCV000279131	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with a history of a Lynch syndrome-related cancer and/or polyps and with a second PMS2 variant in a pediatric patient suspected of having constitutional mismatch repair deficiency (CMMR-D) syndrome (Yurgelun 2015, Adam 2016); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 18602922, 27476653, 28152038, 25980754, 23709753, 27742654, 27064304, 28466842, 26895986, 21376568, 29625052, 30787465, 29752822)
Invitae	RCV000527509	SCV000625573	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the PMS2 mRNA. The next in-frame methionine is located at codon 136. This variant is present in population databases (rs587779333, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individuals with clinical features of Lynch syndrome and constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20487569, 23709753, 24130102, 25559809, 25980754, 27476653; Invitae). ClinVar contains an entry for this variant (Variation ID: 142777). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218553	SCV000889618	pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132181	SCV001343105	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-13	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, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in two individuals affected with PMS2-associated cancer or colorectal polyps (PMID: 25980754, 27476653) and in an individual affected with breast and ovarian cancer (PMID: 24130102). This variant has been identified in 1/250222 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Two different variants, c.1A>G and c.2T>A, that also disrupt the PMS2 translation start codon are known to be pathogenic (Clinvar variation ID: 91323 and 182809, respectively). Loss of PMS2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000218553	SCV002024692	likely pathogenic	not provided	2021-04-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003453093	SCV004187782	pathogenic	Lynch syndrome 4	2023-09-15	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500454	SCV000592914	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The p.Met1 (c.1A>T) variant in exon 1 of the PMS2 gene has not been reported in the literature nor previously identified by our laboratory. This variant did not show up in the databases (dbSNP, NHLBI Exome sequencing project (exome variant server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC) and it is unknown if it may or may not be causative of the disorder. However it causes the loss of the start codon for exon 1. This residue has not been seen in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) and it is unknown if this suggests a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time; however based upon the arguments described above, we find this variant to be PATHOGENIC.