Submissions for variant NM_000535.7(PMS2):c.88C>T (p.Gln30Ter)

dbSNP: rs141577476

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131992	SCV000187050	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	The p.Q30* pathogenic mutation (also known as c.88C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 88. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration has been reported in an individual with endometrial and ovarian cancers with loss of PMS2 on immunohistochemistry (Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9). This alteration was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). 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	RCV000684779	SCV000552069	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln30*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with endometrial and ovarian cancer (PMID: 25856668). ClinVar contains an entry for this variant (Variation ID: 142650). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000521392	SCV000621341	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with endometrial and ovarian cancer, with studied tumors demonstrating loss of PMS2 expression on immunohistochemistry (Goodenberger et al., 2016); This variant is associated with the following publications: (PMID: 25856668, 28152038, 30787465, 31447099, 32719484, 35364342)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000475400	SCV000712559	pathogenic	Lynch syndrome	2016-11-16	criteria provided, single submitter	clinical testing	The p.Gln30X variant in PMS2 has been reported in 2 individuals with Lynch syndr ome-associated cancers (Goodenberger 2015), and was absent from large population studies. This nonsense variant leads to a premature termination codon at positi on 30, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch Syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner.
Color Diagnostics, LLC DBA Color Health	RCV000131992	SCV000905476	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial and ovarian cancer whose tumor showed the loss of PMS2 via immunohistochemistry analysis (PMID: 25856668). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175479	SCV001339068	pathogenic	Hereditary nonpolyposis colon cancer	2020-03-06	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.88C>T (p.Gln30X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245770 control chromosomes. c.88C>T has been reported in the literature in individuals affected with endometrial and/or ovarian cancer (Goodenberger_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197302	SCV001367965	pathogenic	Mismatch repair cancer syndrome 1	2019-01-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310205	SCV001499807	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000521392	SCV002019443	pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000521392	SCV002046224	pathogenic	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. It has been reported in individuals affected with endometrial and/or ovarian cancer in the published literature (PMID: 25856668 (2015)). Therefore, the variant is classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002467441	SCV002762832	pathogenic	Lynch syndrome 4	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_SUP, PM2_SUP
Myriad Genetics, Inc.	RCV002467441	SCV004188569	pathogenic	Lynch syndrome 4	2023-09-18	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.
Baylor Genetics	RCV002467441	SCV004207889	pathogenic	Lynch syndrome 4	2022-07-14	criteria provided, single submitter	clinical testing