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rs121434629

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000535.7(PMS2):c.137G>T(p.Ser46Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,610,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

15
3
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:42O:1

Conservation

PhyloP100: 7.54
Variant links:
Genes affected
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_000535.7
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-6005918-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.949
PP5
Variant 7-6005918-C-A is Pathogenic according to our data. Variant chr7-6005918-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9245.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-6005918-C-A is described in Lovd as [Likely_pathogenic]. Variant chr7-6005918-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMS2NM_000535.7 linkuse as main transcriptc.137G>T p.Ser46Ile missense_variant 2/15 ENST00000265849.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMS2ENST00000265849.12 linkuse as main transcriptc.137G>T p.Ser46Ile missense_variant 2/151 NM_000535.7 P3P54278-1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
40
AN:
245780
Hom.:
0
AF XY:
0.000164
AC XY:
22
AN XY:
134164
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000261
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000282
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000294
AC:
429
AN:
1458548
Hom.:
0
Cov.:
31
AF XY:
0.000258
AC XY:
187
AN XY:
725594
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000358
Gnomad4 OTH exome
AF:
0.000349
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000347
Hom.:
0
Bravo
AF:
0.000128
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000214
AC:
1
ExAC
AF:
0.000128
AC:
15
EpiCase
AF:
0.000218
EpiControl
AF:
0.000356

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:42Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:14
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 27, 2015- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 31, 2023PP4, PP5, PM3_strong, PS3 -
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalFeb 05, 2016- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 23, 2023- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024PMS2: PS3, PS4, PM5 -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 17, 2020In 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. -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 30, 2020Observed 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) -
Likely pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 24, 2018DNA 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). -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 02, 2022The 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 -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Lynch syndrome 4 Pathogenic:10
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineApr 10, 2018This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneApr 19, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2013- -
Likely pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinJul 07, 2020ACMG classification criteria: PS3, PS4, PM1, PM2, PM3 -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylMay 14, 2015- -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 27, 2016Across 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. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 10, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 05, 2023This 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]. -
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalJul 11, 2023The 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. -
Lynch syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 23, 2018The p.Ser46Ile variant in PMS2 has been described as a founder variant for lynch syndrome in Caucasians (Ponti 2015, Tomsic 2013). It has been reported in the h eterozygous state in >15 individuals with Lynch syndrome-associated cancers, whe re the tumors showed microsatellite instability and loss of PMS2 expression in s ome individuals (Borras 2013, Clendenning 2006, Cock-Rada 2017, Haraldsdottir 20 13, Le 2017, Nakagawa 2004, Pritchard 2016, Senter 2008, Tomsic 2013, ClinVar: V ariation ID 9245). This variant has also been reported in the biallelic state (h omozygous or compound heterozygous with a second pathogenic variant) in at least 9 individuals with constitutional mismatch repair deficiency syndrome (CMMRD) a nd segregated with disease in at least 3 affected relatives from at least 2 fami lies (Auclair 2007, Borras 2013, Giunti 2009, Herkert 2011). Normal and tumor ti ssue from some individuals with CMMRD showed loss of expression of PMS2 (Agostin i 2005, Auclair 2007, Bodo 2015, Giunti 2009, Herkert 2011, Jackson 2008, Lavoin e 2015, Pastrello 2011, Stark 2014). Additionally, some relatives who were heter ozygous carriers of this variant were clinically unaffected, suggesting reduced penetrance. In vitro functional studies provide some evidence that the p.Ser46Il e variant may impact protein function (Borras 2013, Drost 2013, Nakagawa 2004). This variant has been identified in 35/122744 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1214346 29). Although this variant has been seen in the general population, its frequenc y is low enough to be consistent with the frequency and penetrance of PMS2-relat ed Lynch syndrome. Computational prediction tools and conservation analysis sugg est that the p.Ser46Ile variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosoma l dominant manner and for CMMRD in an autosomal recessive manner based upon pres ence in multiple affected individuals, segregation studies, and functional evide nce. ACMG/AMP Criteria applied (Richards 2015): PM3_Very_strong; PS3; PS4; PP1; PP3. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 21, 2017Variant 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. -
Likely pathogenic, criteria provided, single submitterclinical testingUniversity of Washington Department of Laboratory Medicine, University of WashingtonNov 20, 2015- -
Likely pathogenic, reviewed by expert panelcurationInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Jun 21, 2019>2 MSI tumours; deficient protein function inferred from 2 independent assays -
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 02, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testingVantari GeneticsJan 26, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Sep 12, 2023- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 02, 2022The p.S46I pathogenic mutation (also known as c.137G>T), located in coding exon 2 of the PMS2 gene, results from a G to T substitution at nucleotide position 137. The serine at codon 46 is replaced by isoleucine, an amino acid with dissimilar properties. 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 M et al. Hum. Mutat. 2006 May;27:490-5; Borras E et al. J. Med. Genet. 2013 Aug;50:552-63; Drost M et al. Hum. Mutat. 2013 Nov;34:1477-80; Dudley B et al. Am. J. Surg. Pathol. 2015 Aug;39:1114-20). 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 J et al. Hum. Mutat. 2007 Nov;28:1084-90; Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Pastrello C et al. Genet. Med. 2011 Feb;13:115-24; Herkert JC et al. Eur. J. Cancer. 2011 May;47:965-82; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8; Rengifo-Cam W et al. ACG Case Rep. J. 2017 Mar;4:e34). Data supports p.S46I as a founder mutation of likely European origin (Tomsic J et al. Clin. Genet. 2013 Mar;83:238-43). Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Lynch syndrome 1 Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Likely pathogenic, criteria provided, single submitterresearchLaan Lab, Human Genetics Research Group, University of TartuMay 01, 2021- -
Breast and/or ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMay 02, 2022- -
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 28, 2022- -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 29, 2024This 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. -
PMS2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 09, 2023The 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. -
Mismatch repair cancer syndrome 4 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2013- -
Pituitary carcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalMar 18, 2016This 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. -
PMS2-related cancer disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-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. -
Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.39
Cadd
Pathogenic
30
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
4.3
H;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.2
D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.98
MVP
0.98
MPC
0.29
ClinPred
0.97
D
GERP RS
5.7
Varity_R
0.99
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121434629; hg19: chr7-6045549; COSMIC: COSV56151410; COSMIC: COSV56151410; API