Submissions for variant NM_000535.7(PMS2):c.2404C>T (p.Arg802Ter)

gnomAD frequency: 0.00001  dbSNP: rs63751466

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076858	SCV000108349	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000129304	SCV000184066	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-08	criteria provided, single submitter	clinical testing	The c.2404C>T (p.R802*) alteration, located in exon 14 (coding exon 14) of the PMS2 gene, consists of a C to T substitution at nucleotide position 2404. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 802. This alteration occurs at the 3' terminus of the PMS2 gene and is not expected to trigger nonsense-mediated mRNA decay; however, it impacts the last 61 amino acids of the PMS2 protein and is expected to result in loss of function by premature protein truncation. This mutation was first reported in an endometrial carcinoma cell line and was observed to result in a truncated protein (Risinger, 1995). Furthermore, this alteration has been reported in multiple individuals with colorectal cancer, whose tumors showed loss of PMS2 on immunohistochemistry (IHC) (Senter, 2008; Rosty, 2016). This alteration has also been reported in a homozygous or compound heterozygous state with another PMS2 mutation in patients whose features include hematologic malignancies, brain tumors, and café-au-lait spots, which are consistent with the phenotype of biallelic PMS2 mutation carriers (De Vos, 2006; Plon, 2011; Andrianova, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Counsyl	RCV000409056	SCV000488733	pathogenic	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000413126	SCV000490734	pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 61 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Observed in the heterozygous state in individuals with Lynch syndrome-related tumors (Senter et al., 2008; Vaughn et al., 2010; Ten Broeke et al., 2015; Rosty et al., 2016; Andrianova et al., 2017; Manchana et al., 2021); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 15077197, 18602922, 18709565, 15340263, 17993636, 25512458, 25525159, 25691505, 17851451, 21376568, 20205264, 21356188, 28514183, 28152038, 26895986, 28805995, 32876971, 32029870, 31433215, 32773772, 30787465, 18619468, Fukui2011[Chapter], 34048176, 33372952, 16507833)
Invitae	RCV000524467	SCV000551948	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg802*) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 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 premature translational stop signal has been observed in individual(s) with Lynch syndrome-related cancers and childhood-onset hematological malignancies and brain tumors (PMID: 15077197, 16507833, 18602922, 25512458, 26110232, 26895986, 28805995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9237). This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Met834Glyfs*17) have been determined to be pathogenic (PMID: 2440087, 10037723, 21618646, 23012243). 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.
Sema4, Sema4	RCV000129304	SCV002530304	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265552	SCV002548074	pathogenic	Hereditary nonpolyposis colon cancer	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2404C>T (p.Arg802X) 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 allele was found at a frequency of 2.7e-05 in 226074 control chromosomes. c.2404C>T has been reported in the literature in heterozygous individuals affected with Lynch syndrome-related cancers (example Senter_2008, Rosty_2016, Suerink_2016, van der Klift_2016, Manchana_2021). In the homozygous state, the variant has also been observed in multiple individuals with early onset brain tumors, leukemias, and lymphomas, often with cooccurring cafe-au-lait spots (example De Vos_2004, De Vos_2006, Andrianova_2017). These data indicate that the variant is very likely to be associated with disease. An endometrial carcinoma cell line with the variant was found to only generate a truncated protein product and was deficient in mismatch repair, suggesting a negative impact on protein function (Risinger_1995). Six 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.
Myriad Genetics, Inc.	RCV000409056	SCV004019877	pathogenic	Lynch syndrome 4	2023-04-05	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.
PreventionGenetics, part of Exact Sciences	RCV003415681	SCV004113956	pathogenic	PMS2-related disorder	2023-05-04	criteria provided, single submitter	clinical testing	The PMS2 c.2404C>T variant is predicted to result in premature protein termination (p.Arg802*). This variant has been reported in individuals with Lynch syndrome (Table 1, Senter et al. 2008. PubMed ID: 18602922; Table S2, ten Broeke et al. 2015. PubMed ID: 25512458; Table S2, Rosty. 2016. PubMed ID: 26895986; Table 1, Okkels et al. 2019. PubMed ID: 31433215; Table 2, Manchana and Triratanachat. 2021. PubMed ID: 34048176). It has been reported in a case of pediatric embryonal rhabdomyosarcoma (Table 3, referred to as 7:6017260G>A, Li et al. 2020. PubMed ID: 33372952). It has also been reported in the homozygous state and presumed compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (De Vos et al. 2004. PubMed ID: 15077197; De Vos et al. 2006. PubMed ID: 16507833; Perez-Valencia et al. 2020. PubMed ID: 32773772; Gupta et al. 2020. PubMed ID: 32876971). This variant is reported in 6 of ~256,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9237/). However, this region has high homology with the pseudogene PMS2CL, and data should be interpreted with caution (http://gnomad.broadinstitute.org/variant/7-6017260-G-A). Nonsense variants in PMS2 are known to be causative. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000409056	SCV004207856	pathogenic	Lynch syndrome 4	2023-04-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076858	SCV004847985	likely pathogenic	Lynch syndrome	2016-07-20	criteria provided, single submitter	clinical testing	The p.Arg802X variant in PMS2 has been reported in 1 heterozygous individual with PMS2-associated tumors and 5 homozygous, consanguineous individuals with cafe-au-lait spots and PMS2-associated tumors. It segregated with disease in 6 affected homozygous siblings from 3 consanguineous families (De Vos 2004 & 2006, Senter 2008). However, none of the heterozygous parents from these consanguineous families had PMS2-associated tumors. Data from large population studies is insufficient to assess the frequency of this variant. This nonsense variant leads to a premature termination codon at position 802. This alteration occurs within the terminal 50 bases of the second to last exon and, therefore, may escape nonsense mediated decay (NMD) resulting in a truncated protein. In vitro functional studies provide some evidence that the p.Arg802X variant may impact protein function (Risinger 1995, Glaab 1998, Peron 2008, Li 2015). Loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg802X variant is likely pathogenic.
OMIM	RCV001267876	SCV000030039	pathogenic	Mismatch repair cancer syndrome 4	2006-03-01	no assertion criteria provided	literature only
Institute of Human Genetics, Medical University Innsbruck	RCV000009818	SCV001431024	pathogenic	Mismatch repair cancer syndrome 1	2020-05-06	no assertion criteria provided	research	This variant, NM_000535.6:c.2404C>T, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.736_741delinsTGTGTGTGAAG. Sample UAB620 in Perez J et al, Genet Med (PMID: 32773772).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257544	SCV001434370	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000409056	SCV002568352	pathogenic	Lynch syndrome 4	2019-10-22	no assertion criteria provided	clinical testing	Seen as heterozygous in individuals with Lynch Syndrome homozygous in individuals with Constitutional Mismatch Repair deficiency.