Submissions for variant NM_000535.7(PMS2):c.631C>T (p.Arg211Ter)

dbSNP: rs760228510

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000222317	SCV000279402	pathogenic	not provided	2022-07-29	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 at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in several individuals with colorectal cancer whose tumors demonstrated absence of PMS2 expression on immunohistochemistry or met Bethesda criteria (Buchanan et al., 2017; Ohmoto et al., 2018; Jiang et al., 2019; Wang et al., 2020); This variant is associated with the following publications: (PMID: 27273229, 28975465, 30521064, 29667044, 31992580, 30787465)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473579	SCV000552000	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg211*) 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 Lynch syndrome (PMID: 27273229). ClinVar contains an entry for this variant (Variation ID: 234508). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000568505	SCV000670743	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The p.R211* pathogenic mutation (also known as c.631C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 631. This changes the amino acid from an arginine to a stop codon within coding exon 6. 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.
Color Diagnostics, LLC DBA Color Health	RCV000568505	SCV000686222	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 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 individuals affected with colorectal cancer (PMID: 27273229, 28975465, 29667044, 30521064) with one individual also affected with pancreatic cancer (PMID: 29667044). 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	RCV001174885	SCV001338298	pathogenic	Lynch syndrome	2020-02-13	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.631C>T (p.Arg211X) 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 251494 control chromosomes. c.631C>T has been reported in the literature in individuals affected with colorectal cancer, pancreatic ductal adenocarcinoma, or breast cancer (Jiang_2019, Buchanan_2016, Ohmoto_2018, Siraj_2017). These data indicate that the variant is likely to be associated with disease. Four 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.
Revvity Omics, Revvity	RCV000222317	SCV003818412	pathogenic	not provided	2022-01-29	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV003315238	SCV004014850	pathogenic	Mismatch repair cancer syndrome 4	2023-07-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454666	SCV004187710	pathogenic	Lynch syndrome 4	2023-09-19	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	RCV003454666	SCV004205343	pathogenic	Lynch syndrome 4	2024-02-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222317	SCV004219018	pathogenic	not provided	2022-01-29	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome and breast cancer, as well as in unaffected controls (PMIDs: 33471991 (2021), 31992580 (2020), 31118792 (2019), 31101557 (2019), 30729418 (2019), 30521064 (2019), 29667044 (2018), 28975465 (2017), 27273229 (2017)). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001174885	SCV004847560	pathogenic	Lynch syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.Arg211X variant in PMS2 has been reported in at least 4 individuals affected with colorectal cancer (Buchanan 2017 PMID: 27273229, Siraj 2017 PMID: 28975465, Ohmoto 2018 PMID: 29667044, Jiang 2019 PMID: 30521064); one of those individuals was also affected with pancreatic cancer (Ohmoto 2018 PMID: 29667044). This variant has also been reported in ClinVar (Variation ID 234508) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 211, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PVS1.
Laboratory for Genotyping Development, RIKEN	RCV003165579	SCV002758157	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research