Submissions for variant NM_000535.7(PMS2):c.825A>G (p.Gln275=)

gnomAD frequency: 0.00001  dbSNP: rs876659736

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219153	SCV000276519	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	The c.825A>G pathogenic mutation (also known as p.Q275Q), located in coding exon 8, results from an A to G substitution at nucleotide position 825 of the PMS2 gene. This nucleotide substitution does not change the amino acid at codon 275. In one study, this alteration was detected in trans with a pathogenic PMS2 mutation in a patient diagnosed with rectal adenomatous polyps, cutaneous lentigines, and hyperpigmentation at age 24 whose family history included a sister with a brain tumor at age 11; these findings are consistent with constitutional mismatch repair deficiency (CMMR-D). RNA analysis of this variant showed abnormal splicing leading to premature protein truncation, and absence of PMS2 by immunohistochemistry was noted in the adenoma, brain tumor, and normal tissues from the proband and the affected sister (Johannesma PC et al. Clin. Genet. 2011 Sep;80:243-55). Additionally, a minigene assay of this variant showed out of frame skipping of the first 22 nucleotides of exon 8, and no full length transcript was produced from the variant allele (van der Klift HM et al. Mol Genet Genomic Med 2015 Jul;3:327-45). This alteration was also reported in conjunction with an alteration in MLH1 (p.Y684D) in a patient diagnosed with colon at 35 years old, belonged to an Amsterdam I family, and showed absent staining of MLH1/PMS2 on IHC (Martin-Morales L et al. PLoS ONE, 2018 Sep;13:e0203885). Of note, this alteration has also been reported in a patient with breast cancer diagnosed at age 52 (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000479060	SCV000568206	likely pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Goodenberger et al., 2016; Suerink et al., 2016; Zhang et al., 2022); Published functional studies demonstrate use of cryptic downstream splice acceptor site resulting in loss of 22 bases and a prematurely truncated transcript (Johannesma et al., 2011; van der Klift et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30256826, 27435373, 21261604, 26247049, 25856668, 28514183, 30787465, 26110232, 30589920, 35477782, 34172528)
Invitae	RCV000541550	SCV000625697	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change affects codon 275 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with Lynch syndrome and symptoms consistent with constitutional mismatch repair deficiency (CMMR-D) (PMID: 21261604, 25856668, 26110232, 28514183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 232390). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763588	SCV000894427	likely pathogenic	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001267893	SCV002762835	likely pathogenic	Lynch syndrome 4	2022-12-09	criteria provided, single submitter	research	PS3, PS4_SUP, PM2_SUP
Baylor Genetics	RCV001267893	SCV004183532	likely pathogenic	Lynch syndrome 4	2023-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001267893	SCV004187563	likely pathogenic	Lynch syndrome 4	2023-09-19	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
Color Diagnostics, LLC DBA Color Health	RCV000219153	SCV004359653	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001267893	SCV001446383	likely pathogenic	Lynch syndrome 4	2019-10-10	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003165571	SCV002758050	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research