Submissions for variant NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)

gnomAD frequency: 0.00018  dbSNP: rs121434629

Total submissions: 45

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076807	SCV000108292	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	>2 MSI tumours; deficient protein function inferred from 2 independent assays
GeneDx	RCV000200994	SCV000149566	pathogenic	not provided	2020-04-30	criteria provided, single submitter	clinical testing	Observed in individuals in the heterozygous state with a personal or family history consistent with pathogenic variants in this gene and reported as a Caucasian founder variant (Nakagawa 2004, Agostini 2005, Clendenning 2006, Auclair 2007, Jackson 2008, Senter 2008, Van der Klift 2010, Herkert 2011, Leenen 2011, Tomsic 2013, Lavoine 2015, Ponti 2015, ten Broeke 2015, Heath 2016, van der Klift 2016, Nowak 2017, Rengifo-Cam 2017); Published functional studies demonstrate a damaging effect: in vitro cell-free complementation assays showed deficient mismatch repair activity as well as reduced PMS2 expression (Nakagawa 2004, Borras 2013, Drost 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25871621, 20186688, 25980754, 26110232, 25345868, 25512458, 28286799, 28528518, 25194673, 22949387, 15256438, 16144131, 16619239, 17557300, 18273873, 18602922, 21376568, 21204794, 22577899, 26318770, 26808570, 27435373, 27863258, 30155321, 23709753, 24027009, 11574484, 24055113, 25637381, 21239990, 26940435, 26143115, 26895986, 26976419, 27433846, 26681312, 28514183, 28365877, 26845104, 28873162, 28904067, 28125078, 27806231, 28152038, 28449805, 26556299, 30013564, 25186627, 29875428, 30702970, 30612635, 31857677, 32060697, 31992580, 31447099, 31433215, 31948886, 31589614, 32719484, 32571878, 33258288, 32634176, 33504652)
Ambry Genetics	RCV000115657	SCV000184825	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-31	criteria provided, single submitter	clinical testing	The c.137G>T (p.S46I) alteration is located in coding exon 2 of the PMS2 gene. This alteration results from a G to T substitution at nucleotide position 137, causing the serine (S) at amino acid position 46 to be replaced by an isoleucine (I). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (48/277180) total alleles studied. The highest observed frequency was 0.031% (11/35326) of Latino alleles. This mutation has been identified in numerous individuals with a tumor exhibiting microsatellite instability and/or loss of PMS2 expression by immunohistochemistry and has been associated with a significant reduction in mismatch repair activity (Clendenning, 2006; Borras, 2013; Drost, 2013; Dudley, 2015). The p.S46I mutation has been reported in a homozygous state or in conjunction with a second PMS2 mutation in multiple individuals with phenotypes consistent with constitutional mismatch repair-deficiency (CMMR-D) (Auclair, 2007; Senter, 2008; Pastrello, 2011; Herkert, 2011; Lavoine, 2015; Rengifo-Cam, 2017). Data supports p.S46I as a founder mutation of likely European origin (Tomsic, 2013). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000200994	SCV000227140	likely pathogenic	not provided	2015-02-27	criteria provided, single submitter	clinical testing
Invitae	RCV000524432	SCV000253845	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 46 of the PMS2 protein (p.Ser46Ile). This variant is present in population databases (rs121434629, gnomAD 0.03%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 16144131, 16619239, 21204794, 21376568, 22577899, 23709753). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9245). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 23709753, 24027009). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076807	SCV000266116	likely pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000115657	SCV000267076	pathogenic	Hereditary cancer-predisposing syndrome	2016-01-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076807	SCV000271259	pathogenic	Lynch syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.Ser46Ile variant in PMS2 has been described as a founder variant for Lynch syndrome in Caucasians (Ponti 2015 PMID:25345868, Tomsic 2013 PMID:22577899). It has been reported in the heterozygous state in >15 individuals with Lynch syndrome-associated cancers, where the tumors showed microsatellite instability and loss of PMS2 expression in some individuals (Borras 2013 PMID:23709753, Clendenning 2006 PMID:16619239, Cock-Rada 2017 PMID:28528518, Haraldsdottir 2013 PMID:25194673, Le 2017 PMID:28596308, Nakagawa 2004 PMID:15256438, Pritchard 2016 PMID:27433846, Senter 2008 PMID:18602922, Tomsic 2013 PMID:22577899, ClinVar: Variation ID 9245). This variant has also been reported in the biallelic state (homozygous or compound heterozygous with a second pathogenic variant) in at least 9 individuals with constitutional mismatch repair deficiency syndrome (CMMRD) and segregated with disease in at least 3 affected relatives from at least 2 families (Auclair 2007 PMID:17557300, Borras 2013 PMID:23709753, Giunti 2009 PMID:19156169, Herkert 2011 PMID:21376568). Normal and tumor tissue from some individuals with CMMRD showed loss of expression of PMS2 (Agostini 2005 PMID:16144131, Auclair 2007 PMID:17557300, Bodo 2015 PMID:26116798, Giunti 2009 PMID:19156169, Herkert 2011 PMID:21376568, Jackson 2008 PMID:18273873, Lavoine 2015 PMID:26318770, Pastrello 2011 PMID:21239990, Stark 2014 PMID:24897087). Additionally, some relatives who were heterozygous carriers of this variant were clinically unaffected, suggesting reduced penetrance. In vitro functional studies provide some evidence that the p.Ser46Ile variant may impact protein function (Borras 2013 PMID:23709753, Drost 2013 PMID:24027009, Nakagawa 2004 PMID:15256438). This variant has been identified in 0.04% (416/1179868) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the frequency and penetrance of PMS2-associated Lynch syndrome. Computational prediction tools and conservation analysis suggest that the p.Ser46Ile variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome (ACMG/AMP Criteria applied: PS3; PS4; PP1; PP3) and for autosomal recessive CMMRD (ACMG/AMP Criteria applied: PM3_Very_strong; PS3; PP1; PP3).
Illumina Laboratory Services, Illumina	RCV000056324	SCV000469744	likely pathogenic	Lynch syndrome 4	2016-09-27	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the PMS2 c.137G>T (p.Ser46Ile) missense variant has been identified in at least 18 heterozygous or compound heterozygous cases with various cancers and three as-yet unaffected heterozygous family members (Agostini et al. 2005; Auclair et al. 2007; Senter et al. 2008; Pastrello et al. 2011; Herkert et al. 2011; Tomsic et al. 2013; Borras et al. 2013). The p.Ser46Ile variant was absent from 188 control individuals and 436 control chromosomes but is reported at a frequency of 0.00022 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant occurs at a strongly conserved residue in an important functional domain. Borras et al. (2013) demonstrated through in vitro expressions studies that the p.Ser46Ile variant had significantly reduced mismatch repair activity, approximately 13% that of wild type, while Drost et al. (2013) showed that the p.Ser46Ile variant had a mismatch repair efficiency similar to that of a known pathogenic variant. Based on the evidence, the p. Ser46Ile variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000200994	SCV000601815	pathogenic	not provided	2020-04-17	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in multiple families with Lynch syndrome as well as in individuals with biallelic pathogenic variants who have been diagnosed with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMIDs: 30702970 (2019), 21239990 (2011), 20205264 (2010), 16144131 (2005)). Additionally, functional studies have shown this variant causes significantly reduced DNA mismatch repair activity in vitro (PMID: 23709753 (2013)). The frequency of this variant in the general population, 0.00031 (11/35326 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000200994	SCV000604885	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	The PMS2 c.137G>T; p.Ser46Ile variant (rs121434629) is published in the literature in individuals and families with Lynch syndrome-associated cancers and constitutional mismatch repair-deficiency (Auclair 2007, Borras 2013, Jackson 2008, Senter 2008, Tosmic 2013). This variant is reported in ClinVar (Variation ID: 9245) and is found in the Latino population with an overall allele frequency of 0.03% (11/35,326 alleles) in the Genome Aggregation Database. Several individuals with constitutional mismatch repair-deficiency carried this variant in trans to a pathogenic PMS2 variant (Auclair 2007, Jackson 2008, Senter 2008), including another variant at the same codon, p.Ser46Asn, observed in two affected individuals (Jackson 2008, Senter 2008). The serine at codon 46 is highly conserved and both the p.Ser46Ile and p.Ser46Asn variants exhibit less than 10% of wild-type activity in mismatch repair in vitro assays (Borras 2013, Drost 2013). Based on available information, this variant is considered to be pathogenic. References: Auclair J et al. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007 Nov;28(11):1084-90. PMID: 17557300 Borras E et al. Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet. 2013 Aug;50(8):552-63. PMID: 23709753 Drost M et al. Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene. Hum Mutat. 2013 Nov;34(11):1477-80. PMID: 24027009 Jackson CC et al. Cafe-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2. Pediatr Blood Cancer. 2008 Jun;50(6):1268-70. PMID: 18273873 Senter L et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008 Aug;135(2):419-28. PMID: 18602922 Tomsic J et al. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013 Mar;83(3):238-43. PMID: 22577899
Counsyl	RCV000056324	SCV000677739	likely pathogenic	Lynch syndrome 4	2015-05-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115657	SCV000686122	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 46 in the nucleotide binding pocket of the ATPase domain of the PMS2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant significantly impairs the mismatch repair activity of PMS2 protein (PMID: 23709753, 24027009). This variant has been reported in over 50 individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 15256438, 16619239, 18602922, 23709753, 28596308, 30702970, 31992580) and is thought to be a founder mutation in the Caucasian population (PMID: 22577899, 25345868). This variant has been reported in trans with pathogenic PMS2 variants in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 16144131, 17557300, 21204794, 21376568). This variant has been identified in 48/277180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000056324	SCV000803859	likely pathogenic	Lynch syndrome 4	2017-04-19	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000056324	SCV000840051	pathogenic	Lynch syndrome 4	2018-04-10	criteria provided, single submitter	clinical testing	This c.137G>T (p.S46I) variant in PMS2 has been reported in individuals with mismatch repair deficiency syndrome, colon, endometrial, colorectal and bladder cancer (PMID: 21376568, 16144131, 21204794, 22577899, 16619239, 23709753). In addition, functional studies have shown that the c.137G>T (p.S46I) variant significantly impairs mismatch repair activity (PMID: 23709753, 24027009). Therefore, the c.137G>T (p.S46I) in the PMS2 gene is classified as pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722017	SCV000853190	likely pathogenic	Pituitary carcinoma	2016-03-18	criteria provided, single submitter	clinical testing	This is a missense variant in which a G is replaced by a T at coding position 137 and is predicted to change a Serine to an Isoleucine at codon 46.
Fulgent Genetics, Fulgent Genetics	RCV002476951	SCV000894431	pathogenic	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076807	SCV000918033	pathogenic	Lynch syndrome	2017-11-21	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.137G>T (p.Ser46Ile) variant involves the alteration of a conserved nucleotide that results in a missense change within the nucleotide binding pocket of the ATPase domain (Borras 2013). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies have shown the variant to cause deficient MMR activity (Borras 2013, Drost 2013, van der Klift 2016). This variant was found in 47/271742 control chromosomes (in gnomAD and publication controls), however the technology utilized for the gnomAD dataset does not rule out pseudogene interference and thus this data cannot be relied upon. This variant has been reported in several patients/families with Lynch syndrome-associated cancers (in many cases isolated loss of PMS2 was detected in the tumors) as well as in patients with constitutional MMR deficiency (CMMR-D) syndrome who also have a second pathogenic PMS2 mutation (in many of these cases PMS2 loss in normal tissues was documented) (Clendenning 2006, Senter 2008, Herkert_2011, Tomsic 2013, Borras 2013, van der Klift 2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000056324	SCV001137331	likely pathogenic	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000200994	SCV001450303	likely pathogenic	not provided	2016-02-05	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000200994	SCV002009116	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000200994	SCV002018884	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797999	SCV002042783	likely pathogenic	Breast and/or ovarian cancer	2022-05-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200994	SCV002072174	likely pathogenic	not provided	2018-09-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.137G>T, in exon 2 that results in an amino acid change, p.Ser46Ile. The p.Ser46Ile change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Ser46Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL), and has been described in the EXAC database with a low population frequency of 0.013% (dbSNP rs121434629). This particular amino acid change has been described in the literature in the homozygous and compound heterozygous states in patients with autosomal recessive constitutional mismatch repair deficiency syndrome (PMIDs: 21204794, 16144131, 21376568). This variant was also reported in 2 members of a family affected with lynch syndrome associated colorectal and skin tumors, and bladder cancer (PMID: 23709753). In vitro functional assays demonstrate decreased mismatch repair activity for the Ser46Ile variant compared to wild type (PMID: 23709753).
CeGaT Center for Human Genetics Tuebingen	RCV000200994	SCV002497503	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PMS2: PS3, PS4, PM5
Laan Lab, Human Genetics Research Group, University of Tartu	RCV001804723	SCV002538616	likely pathogenic	Lynch syndrome 1	2021-05-01	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000056324	SCV004019868	pathogenic	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26116798, 26318770, 17557300, 32642664, 30608896]. Functional studies indicate this variant impacts protein function [PMID: 24027009, 23709753, 27435373, 30608896, 17557300]. This variant is expected to disrupt protein structure [Myriad internal data].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000056324	SCV004031230	pathogenic	Lynch syndrome 4	2023-07-11	criteria provided, single submitter	clinical testing	The PMS2 c.137G>T (p.Ser46Ile) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies support that the variant impairs mismatch repair activity (PMID: 23709753). This variant has been observed in several individuals with features consistent with Lynch syndrome and constitutional mismatch repair deficiency, including tumors that have demonstrated microsatellite instability and/or loss of PMS2 by immunohistochemistry (PMID: 17557300, 18273873, 19156169, 19283792, 20205264). In summary, this variant meets criteria to be classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335023	SCV004046408	pathogenic	PMS2-related cancer disorders		criteria provided, single submitter	clinical testing	This variant has been reported in the heterozygous state in individuals affected with Lynch syndrome-associated cancers (PMID: 15256438, 16619239, 18602922, 23709753, 28596308, 30702970, 31992580) and in the homozygous or compound heterozygous state in individuals affected with constitutional mismatch repair deficiency syndrome (CMMRD) (PMID: 16144131, 17557300, 21204794, 21376568). In vitro experimental studies have shown that this variant impairs the mismatch repair activity of PMS2 (PMID: 23709753, 24027009). The c.137G>T(p.Ser46Ile) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (48/277180) and is absent in the homozygous state. The c.137G>T(p.Ser46Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.137G>T(p.Ser46Ile) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390667	SCV004121118	pathogenic	PMS2-related disorder	2023-02-09	criteria provided, single submitter	clinical testing	The PMS2 c.137G>T variant is predicted to result in the amino acid substitution p.Ser46Ile. This variant has been reported as a founder variant in European populations (Table 1, Senter et al. 2008. PubMed ID: 18602922; Tomsic et al. 2013. PubMed ID: 22577899; Table 1 and Figure 2, Wang et al. 2020. PubMed ID: 31992580). It has been reported in the heterozygous state in individuals with Lynch syndrome spectrum cancers (Clendenning et al. 2006. PubMed ID: 16619239; Fanale et al. 2022. PubMed ID: 35223509; Table S1, S3, Susswein et al. 2016. PubMed ID: 26681312; Tomsic et al. 2013. PubMed ID: 22577899; Cock-Rada et al. 2018. PubMed ID: 28528518; Brohl et al. 2017. PubMed ID: 28125078; Table S4, Hartman. 2020. PubMed ID: 32782288; Hechtman et al. 2020. PubMed ID: 31857677). This variant has also been reported in the homozygous and compound heterozygous states in individuals with autosomal recessive constitutional mismatch repair-deficiency syndrome (Agostini et al. 2005. PubMed ID: 16144131; Table 1, Herkert et al. 2011. PubMed ID: 21376568). Of note, this variant has also been reported in cis (on the same allele) with a second pathogenic PMS2 variant, c.164–1G>A, in individuals with autosomal dominant Lynch syndrome and is referred to as the c.[137G>T; 164-1G>A] allele (Table 1 and Figure 2, Wang et al. 2020. PubMed ID: 31992580). The c.137G>T (p.Ser46Ile) variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6045549-C-A) and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9245/). This variant, in isolation or as the c.[137G>T; 164-1G>A] allele, is interpreted as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000056324	SCV004183374	likely pathogenic	Lynch syndrome 4	2020-07-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM1, PM2, PM3
Baylor Genetics	RCV000056324	SCV004205401	pathogenic	Lynch syndrome 4	2023-10-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000200994	SCV004223967	pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	PP4, PP5, PM3_strong, PS3
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115657	SCV004228118	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076807	SCV004842155	pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	The c.137G>T (p.Ser46Ile) variant in the PMS2 gene is located on the exon 2 and is predicted to replace serine with isoleucine at codon 46 (p.Ser46Ile). The variant has been reported in more than 10 unrelated individuals affected with Lynch syndrome in heterozygous state (PMID: 18602922, 27435373, 21204794, 32634176). A different missense variant affecting the same amino acid (p.Ser46Asn) has been interpreted as pathogenic (ClinVar ID: 91301). The variant has been reported in more than 10 unrelated individuals with constitutional mismatch repair-deficiency (CMMRD) syndrome in homozygous or compound heterozygous states (PMID: 21204794, 32642664, 26318770). The variant was detected in trans with other pathogenic variants (p.Pro246fs, p.Arg578fs) in individuals with CMMRD (ClinVar ID: 91366, 9244, PMID: 21204794, 32642664). Experimental studies showed this variant resulted in impaired mismatch repair activity and negative functional impact on the protein (PMID: 23709753, 24027009). The variant is reported in ClinVar (ID: 9245). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.939). Therefore, the c.137G>T (p.Ser46Ile) variant of PMS2 has been classified as pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555831	SCV005045097	pathogenic	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2023-11-15	criteria provided, single submitter	clinical testing	The PMS2 c.137G>T (p.Ser46Ile) variant has been reported in a number individuals affected with Lynch syndrome (Borras E et al., PMID: 23709753; Senter L et al., PMID: 18602922; Tosmic J et al., PMID: 22577899) or mismatch repair cancer syndrome (Agostini M et al., PMID: 16144131; Herkert JC et al., PMID: 21376568; Leenen CHM et al., PMID: 21204794) and is reported to segregate with disease in families. Functional studies show deficient mismatch repair activity, indicating that this variant impacts protein function (Borras E et al., PMID: 23709753; Drost M et al., PMID: 24027009; van der Klift HM et al., PMID: 27435373). This variant resides within the nucleotide binding pocket of the ATPase domain, suggesting an interference with the ATPase function (Borras E et al., PMID: 23709753). Another variant in the same codon, c.137G>A (p.Ser46Asn), has been reported in affected individuals with Lynch syndrome and is considered pathogenic (Everett JN et al., PMID: 25006859; Haraldsdottir S et al., PMID: 26866578, ClinVar Variation ID: 91301). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.03% in Latino/Admixed American population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMS2 function. This variant has been reported in the ClinVar database as a pathogenic variant by 20 submitters and likely pathogenic by 16 submitters (ClinVar Variation ID: 9245). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
OMIM	RCV001267878	SCV000030047	pathogenic	Mismatch repair cancer syndrome 4	2013-08-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000009826	SCV000190470	pathogenic	Mismatch repair cancer syndrome 1	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353458	SCV000592923	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PMS2 p.Ser46Ile variant was identified in 11 of 1466 proband chromosomes (frequency: 0.008) from individuals or families with hereditary breast and ovarian cancer syndrome or Lynch syndrome and was not identified in 2490 control chromosomes from healthy individuals (Bodo 2017, Borras 2013, Clendenning 2006, Senter 2008, Pastrello 2011, Dorschner 2013, Nakagawa 2004). The variant was also identified in dbSNP (ID: rs121434629) as “With Pathogenic, Uncertain significance allele”, ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 other submitters; and as likely pathogenic by InSiGHT expert panel in 2014 and 7 other submitters), COGR (2x), Insight Colon Cancer Gene Variant Database (1x as class 4), Mismatch Repair Genes Variant Database (4x), and Insight Hereditary Tumors Database (25x). The variant was not identified in Cosmic or Zhejiang Colon Cancer Database. The variant was identified in control databases in 48 of 277180 chromosomes at a frequency of 0.0002 (Genome Aggregation Consortium Feb 27, 2017), in the following populations: Latino in 11 of 35326 chromosomes (frequency: 0.0003) and European in 37 of 125388 chromosomes (frequency: 0.0003); it was not identified in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was identified in several cases with CMRD or Turcot syndrome as a biallelic variant with one of the following PMS2 variants: c.1951C>T, c.2174+1G>A, c.804-2A>G, and c.137G>A (Agostini 2005, Herkert 2011, Giunti 2009, Jackson 2008, Senter 2008). The variant is located within the functional domain of histidine kinase-like ATPase, increasing the likelihood that it may have clinical significance. Functional assays have shown that this variant had reduced mismatch repair efficiency (Drost 2013) and resulted in near absence of the PMS2 protein (Auclair 2007). One study suggests that this variant may by a founder mutation in a population of undetermined ancestry (Tomsic et al 2013). This variant has also been identified by our laboratory in two patients affected with Lynch syndrome and PMS2-deficient colon tumours. The p.Ser46 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that this variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000200994	SCV001800634	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000200994	SCV001918197	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000200994	SCV001956600	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000200994	SCV001976325	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001804723	SCV002054088	not provided	Lynch syndrome 1		no assertion provided	literature only
OMIM	RCV000056324	SCV002601716	pathogenic	Lynch syndrome 4	2013-08-01	no assertion criteria provided	literature only