Submissions for variant NM_000535.7(PMS2):c.325dup (p.Glu109fs)

dbSNP: rs587781716

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218863	SCV000277647	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The c.325dupG pathogenic mutation, located in coding exon 4 of the PMS2 gene, results from a duplication of G at nucleotide position 325, causing a translational frameshift with a predicted alternate stop codon (p.E109Gfs*30). This variant has also been shown to be associated with abnormal splicing resulting in transcripts containing out-of-frame full or partial deletion of coding exon 4 (van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3(4):327-45; Ambry internal data). This variant has been identified in several probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability (MSI-H) and/or isolated loss of PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). This variant has been reported in an individual diagnosed with colon cancer at age 40 whose tumor showed loss of PMS2 staining on IHC (Vaughn CP et al. Hum. Mutat. 2010 May;31(5):588-93). This variant was also identified in trans with another pathogenic PMS2 mutation in two siblings with constitutional mismatch repair-deficiency (CMMR-D) syndrome. One sibling was diagnosed with a brain tumor at age 11 while the other was diagnosed with rectal adenomas at age 24, lentigines, and hyperpigmentation (Johannesma PC et al. Clin. Genet. 2011 Sep;80(3):243-55). In another study, this pathogenic mutation was reported in individuals with colon cancer and pituitary cancer (Goodenberger ML et al. Genet. Med. 2016 Jan;18(1):13-9). This variant was also reported in a proband with MSI-H colorectal cancer diagnosed at age 38 that demonstrated positive mismatch repair protein staining on IHC (Jansen AML et al. Eur J Hum Genet, 2020 03;28:333-338). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000536196	SCV000625635	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049). ClinVar contains an entry for this variant (Variation ID: 233300). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or constitutional mismatch repair deficiency (PMID: 20205264, 21261604). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762485848, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Glu109Glyfs*30) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
GeneDx	RCV000657178	SCV000778899	pathogenic	not provided	2019-07-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28637615, 20205264, 21261604, 25856668, 26110232, 26247049, 31616036, 31447099)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709752	SCV000840044	pathogenic	Lynch syndrome 4	2017-05-11	criteria provided, single submitter	clinical testing	This c.325dup (p.Glu109Glyfs*30) variant has been reported in a cohort of 145 unrelated patients with colorectal cancer [PMID 20205264]. This variant has been observed in 3 heterozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/7-6043348-T-TC). This 1bp duplication creates a frameshift and is predicted to create a premature stop codon 30 amino acid downstream, and to result in a loss of function of the PMS2 protein. This variant is thus classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000218863	SCV000909678	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 4 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with Lynch syndrome or colorectal cancer (PMID: 20205264, 25856668, 31616036). This variant has also been reported in siblings affected with constitutional mismatch repair deficiency (CMMRD) who carried a PMS2 variant in trans (PMID: 21261604). This variant has been identified in 4/236098 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000657178	SCV003818345	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000709752	SCV004188614	pathogenic	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000709752	SCV004205436	pathogenic	Lynch syndrome 4	2023-09-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998544	SCV004842127	pathogenic	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. Functional studies suggest that this variant may have a splice effect predicted to result in loss-of-function, in addition to the frameshift effect (PMID: 26247049). This variant has been reported as heterozygous in multiple individuals with PMS2-related cancers (PMID: 20205264, 25856668, 31616036, 35739278). In addition, it has been reported in the compound heterozygous state in siblings with constitutional mismatch repair deficiency (PMID: 21261604). This variant is present in 4/236098 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/).