Submissions for variant NM_000535.7(PMS2):c.3G>A (p.Met1Ile)

dbSNP: rs1554309086

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519055	SCV000619402	pathogenic	not provided	2020-11-13	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29485237, 28514183, 28466842, 27742654)
Invitae	RCV000535555	SCV000625651	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-06-01	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the PMS2 mRNA. The nearest in-frame methionine that could be used to initiate PMS2 translation occurs at codon 136, and therefore this variant is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Two different variants (c.1A>G and c.2T>A) that also disrupt the PMS2 initiator codon have been reported in individuals with colorectal, endometrial, and breast cancer (PMID: 20487569, 23709753, 25559809, Invitae).  Additionally, these variants have been reported in individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMID: 18602922). The two variants have been determined to be pathogenic, suggesting that other substitutions at this position may also be pathogenic. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 450786). This variant is not present in population databases (ExAC no frequency).
Ambry Genetics	RCV000569016	SCV000674255	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-03	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.3G>A), located in coding exon 1 of the PMS2 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). 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.
Myriad Genetics, Inc.	RCV003449491	SCV004187664	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].
Color Diagnostics, LLC DBA Color Health	RCV000569016	SCV004359724	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon (methionine at codon 1) of the PMS2 gene. This variant is expected to disrupt the expression of the full-length PMS2 protein. The next in-frame methionine occurs at codon 136, and it is not known if a functional PMS2 protein product can be produced using p.Met136 as an alternative translation start site. To our knowledge, functional studies have not been reported for this variant. This nucleotide change has not been reported in the literature, however, other variants resulting in a start loss at codon 1 have been observed in individuals affected with Lynch syndrome-associated disease (ClinVar ID: 91323, 142777, 182809). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.