Submissions for variant NM_000535.7(PMS2):c.400C>T (p.Arg134Ter)

gnomAD frequency: 0.00001  dbSNP: rs63750871

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076872	SCV000108365	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000212842	SCV000149604	pathogenic	not provided	2023-07-07	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; Observed in the heterozygous state in individuals with a personal or family history consistent with pathogenic variants in this gene (Senter 2008, Vaughn 2013, Rosty 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17993636, 19495563, 26720728, 29922827, 31447099, 25525159, 7661930, 15845562, 16284300, 26318770, 26270727, 7632227, 18602922, 23012243, 9488480, 16283678, 21376568, 25850602, 12714694, 26895986, 28152038, 18709565, 15077197, 30322717, 32719484, 30787465, 33087929, 35449176, 36988593)
Invitae	RCV000524474	SCV000166386	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg134*) 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 present in population databases (rs63750871, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency, colorectal cancer, Lynch syndrome, and ovarian cancer (PMID: 15077197, 18602922, 23012243, 25850602, 26318770, 26681312, 26895986). ClinVar contains an entry for this variant (Variation ID: 9234). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 7632227, 9488480, 12714694). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115695	SCV000187198	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-06	criteria provided, single submitter	clinical testing	The p.R134* pathogenic mutation (also known as c.400C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 400. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been identified in multiple individuals with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome caused by biallelic PMS2 mutations (Hamilton SR et al. N. Engl. J. Med. 1995 Mar;332:839-47; De Vos M et al. Am. J. Hum. Genet. 2004 May;74:954-64; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This mutation has also been identified in multiple patients with Lynch syndrome-associated tumors that showed isolated loss of PMS2 protein expression on IHC (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This alteration has also been detected in 1/1915 women with ovarian cancer, unselected for family history (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90). 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.
Counsyl	RCV000576870	SCV000677741	pathogenic	Lynch syndrome 4	2017-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115695	SCV000686201	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076872	SCV000713220	pathogenic	Lynch syndrome	2021-10-27	criteria provided, single submitter	clinical testing	The p.Arg134X variant in PMS2 has been reported in at least 6 families (7 individuals) with PMS2-associated cancers (Parsons 1995 PMID: 7632227, Norquist 2016 PMID: 26720728, Rosty 2016 PMID: 26895986, LaDuca 2017 PMID: 28152038, Carter 2018 PMID: 30322717) and in the compound heterozygous state in 2 families (3 individuals) with constitutional mismatch repair disease (CMMRD; De Vos 2004 PMID: 15077197, Lavoine 2015 PMID: 26318770). It has also been identified in 1/128850 of European and 1/35440 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 134, 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 vitro functional studies support an impact on protein function (Parsons 1995 PMID: 7632227, Nicolaides 1998 PMID: 9488480, Gibson 2006 PMID: 16426742). In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108365.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate, PS3_Moderate.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000576870	SCV000840047	pathogenic	Lynch syndrome 4	2017-09-19	criteria provided, single submitter	clinical testing	The c.400C>T (p.R134*) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with constitutional mismatch repair deficiency syndrome as well as in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 15077197, 18602922, 23012243, 26681312, 26895986). The c.400C>T (p.R134*) variant in the PMS2 gene is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212842	SCV000889627	pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282538 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 26895986 (2016), 18602922 (2008)), Turcot syndrome (PMIDs: 15077197 (2004), 7661930 (1995)), ovarian cancer (PMIDs: 30322717 (2018), 26720728 (2016), 26681312 (2015)), and breast cancer (PMID: 35449176 (2022)). It has also been identified in individuals with CMMRD (PMIDs: 26318770 (2015), 25850602 (2015), 15077197 (2004)). Functional studies indicate this variant causes impaired DNA mismatch repair activity (PMIDs: 9488480 (1998), 7632227 (1995)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076872	SCV000918060	pathogenic	Lynch syndrome	2018-07-13	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.400C>T (p.Arg134X) 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 (eg. c.697C>T, p.Gln233X; c.736_741delinsTGTGTGTGAAG, p.Pro246fsX3). The variant allele was found at a frequency of 8.2e-06 in 121392 control chromosomes. c.400C>T has been reported in the literature in individuals affected with Turcot syndrome who carry a second pathogenic variant (DeVos_2004) and in patients with Lynch Syndrome and colorectal cancer (Senter_2008, Durno_2005). These data indicate that the variant is likely to be associated with disease. Additionally, this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism. 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196700	SCV001367331	pathogenic	Mismatch repair cancer syndrome 1	2019-11-13	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310204	SCV001499806	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115695	SCV002530343	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	curation
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000576870	SCV002762834	pathogenic	Lynch syndrome 4	2022-12-09	criteria provided, single submitter	research	PVS1, PS3, PS4_STR, PM2_SUP
Revvity Omics, Revvity	RCV000212842	SCV003818434	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576870	SCV004019879	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.
Baylor Genetics	RCV000576870	SCV004207883	pathogenic	Lynch syndrome 4	2022-10-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076872	SCV004839977	pathogenic	Lynch syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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.
OMIM	RCV000009815	SCV000030036	pathogenic	Mismatch repair cancer syndrome 4	2004-05-01	no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162222	SCV002758052	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research