rs121434629

chr7-6005918-C-Achr7-6005918-C-Gchr7-6005918-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:44 O:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

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
PMS2	NM_000535.7	c.137G>T	p.Ser46Ile	missense_variant	2/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.137G>T	p.Ser46Ile	missense_variant	2/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152222 Hom.: 0 Cov.: 33

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

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

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

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:44 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2022	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 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PMS2: PS3, PS4, PM5 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2023	PP4, PP5, PM3_strong, PS3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2018	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Lynch syndrome 4 Pathogenic:10

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 07, 2020	ACMG classification criteria: PS3, PS4, PM1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 11, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	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]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 27, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 10, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Apr 19, 2017	- -

Lynch syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2017	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. -
Likely pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 21, 2019	>2 MSI tumours; deficient protein function inferred from 2 independent assays -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2024	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 26, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 12, 2023	- -

Lynch syndrome 1 Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 02, 2022

- -

PMS2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2023

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. -

Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Nov 15, 2023

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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2022

- -

Mismatch repair cancer syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2013

- -

Pituitary carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Mar 18, 2016

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. -

PMS2-related cancer disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady 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 provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department 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

Other links and lift over

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