Submissions for variant NM_000535.7(PMS2):c.2506G>T (p.Glu836Ter)

dbSNP: rs786201039

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162416	SCV000212756	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-10	criteria provided, single submitter	clinical testing	The p.E836* pathogenic mutation (also known as c.2506G>T), located in coding exon 15 of the PMS2 gene, results from a G to T substitution at nucleotide position 2506. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000657711	SCV000779460	likely pathogenic	not provided	2017-11-22	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2506G>T at the cDNA level and p.Glu836Ter (E836X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through protein truncation. Even though this variant occurs near the end of the gene and nonsense-mediated decay is not expected to occur, it is significant since the last 26 amino acids are no longer translated. Furthermore, the truncation would disrupt a portion of the endonuclease domain and a conserved Zinc binding motif (Kosinski 2008, Fukui 2011). Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657711	SCV001134597	likely pathogenic	not provided	2019-01-25	criteria provided, single submitter	clinical testing	Not found in the gnomAD exomes dataset, and the data is high quality (0/159092 chr). Found in at least one symptomatic patient. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae	RCV001066692	SCV001231708	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-07-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 26116798, 30764633). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant disrupts the C-terminal portion of the MLH1 interaction domain (amino acids 675-850) of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 183718). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28514183). The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change creates a premature translational stop signal (p.Glu836*) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the PMS2 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317111	SCV004020712	pathogenic	Hereditary nonpolyposis colon cancer	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2506G>T (p.Glu836X) results in a premature termination codon in the last exon of PMS2, and is predicted to cause a truncation of the last 27 amino acids of the PMS2 protein. Other truncating variants in this region have been classified as pathogenic in ClinVar. Additionally, this region of the protein (amino acids 675 - 850) has been shown to be critical for interaction between PMS2 and MLH1 (PMID: 10037723). The variant was absent in 167792 control chromosomes in GnomAD. However, the region is highly homologous to PMS2 pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference, therefore these data might not be reliable for assessing variant frequency. c.2506G>T has been reported in the literature in an individual affected with Lynch Syndrome (Espenschied_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003454389	SCV004188616	pathogenic	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.