Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
AIMP2 (HGNC:20609): (aminoacyl tRNA synthetase complex interacting multifunctional protein 2) The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex. [provided by RefSeq, May 2016]
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 136 codons. Genomic position: 6002584. Lost 0.157 part of the original CDS.
PS1
Another start lost variant in NM_000535.7 (PMS2) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-6009019-T-G is Pathogenic according to our data. Variant chr7-6009019-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 820477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant disrupts the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The frequency of this variant in the general population, 0.000032 (1/31402 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has not been reported in individuals with a PMS2-related disorder. However, other start loss variants affecting the same codon have been reported in affected patients with suspected Lynch Syndrome (PMIDs: 18602922 (2008), 23709753 (2014), 27742654 (2017), and 28466842 (2017)). Based on the available information, this variant is classified as likely pathogenic. -
Jun 23, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Hereditary nonpolyposis colon cancer Pathogenic:1
Sep 18, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: PMS2 c.1A>C (p.Met1Leu) 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. Two of three in-silico tools predict a benign effect of the variant on protein function. The next downstream in-frame ATG start site is at codon 136 (Exon 5). Other variants impacting the PMS2 initiation codon, including c.1A>G (p.Met1Val), c.2T>C (p.Met1Thr), and c.2T>A (p.Met1Lys), as well as missense and truncating variants upstream of the potential new initiation codon have been classified as pathogenic by our lab and in ClinVar, and reported in association with Lynch syndrome-associated cancers in HGMD. The variant was absent in 250222 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1A>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: 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 (no rsID available, gnomAD 0.03%). Disruption of the initiator codon has been observed in individuals with PMS2-related conditions (PMID: 18602922, 20487569, 23709753; Invitae). ClinVar contains an entry for this variant (Variation ID: 820477). For these reasons, this variant has been classified as Pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.M1? pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the PMS2 gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). 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, J. Med. Genet. 2013 Aug; 50(8):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. -
Lynch syndrome 4 Pathogenic:1
Sep 15, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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]. -