Submissions for variant NM_000535.7(PMS2):c.2533del (p.His845fs)

dbSNP: rs1064796500

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479133	SCV000573284	likely pathogenic	not provided	2024-08-20	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 18 amino acids are replaced with 5 different amino acids, and other similar variants have been reported in HGMD; Disrupts the critical zinc binding conserved motif (CPHGRP) of the endonuclease domain (PMID:18619468); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Fukui2011[Chapter], 18619468)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780639	SCV000918070	likely pathogenic	Lynch syndrome	2018-12-04	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2533delC (p.His845MetfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 183842 control chromosomes. To our knowledge, no occurrence of c.2533delC in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001015794	SCV001176669	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-28	criteria provided, single submitter	clinical testing	The c.2533delC pathogenic mutation, located in coding exon 15 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 2533, causing a translational frameshift with a predicted alternate stop codon (p.H845Mfs*6). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of PMS2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 13 amino acids of the protein. However, structural analysis suggests this alteration would disrupt the zinc binding motif, which is required for in vivo MMR activity, and the MLH1 interface of the exonuclease domain (Kosinski J et al. J. Mol. Biol. 2008 Oct;382:610-27; Fukui K et al. J. Biol. Chem. 2008 May;283:12136-45; Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr;20:461-8). In addition, this variant been identified as homozygous in an individual with very early onset colon and ovarian cancers demonstrating loss of PMS2 protein expression by IHC (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003449244	SCV004187621	likely pathogenic	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090975	SCV005796575	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His845Metfs*6) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the PMS2 protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 423571). This variant disrupts a region of the PMS2 protein in which other variant(s) (p.846*) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.