ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.137G>T (p.Ser46Ile) (rs121434629)

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Total submissions: 25
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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 2018-09-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.137G>T at the cDNA level, p.Ser46Ile (S46I) at the protein level, and results in the change of a Serine to an Isoleucine (AGT>ATT). PMS2 Ser46Ile was observed at an allele frequency of 0.03% (11/34312) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in Motif I of the ATPase domain (Guarne 2001). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. PMS2 Ser46Ile has been published in the literature as a Caucasian founder pathogenic variant (Senter 2008, Tomsic 2013, Ponti 2015). It has been reported in many individuals with Lynch syndrome-associated tumors and in many individuals with autosomal recessive constitutional mismatch repair deficiency syndrome (CMMR-D) in the homozygous state or in the compound heterozygous state with a second PMS2 pathogenic variant on the opposite chromosome. Tumor testing in many of these individuals showed microsatellite instability (MSI-H) and/or loss of PMS2 protein expression (Nakagawa 2004, Agostini 2005, Clendenning 2006, Auclair 2007, Jackson 2008, Senter 2008, Van der Klift 2010, Hekert 2011, Leenen 2011, Lavoine 2015, ten Broeke 2015, Heath 2016, Nowak 2016, van der Klift 2016, Rengifo-Cam 2017). While some functional studies have been inconclusive, several independent in vitro cell-free complementation assays showed deficient mismatch repair activity as well as reduced PMS2 expression (Nakagawa 2004, Borras 2013, Drost 2013). Based on currently available evidence, we consider PMS2 Ser46Ile to be a pathogenic variant.
Ambry Genetics RCV000115657 SCV000184825 pathogenic Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing The 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000200994 SCV000227140 likely pathogenic not provided 2015-02-27 criteria provided, single submitter clinical testing
Invitae RCV000524432 SCV000253845 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 46 of the PMS2 protein (p.Ser46Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs121434629, ExAC 0.02%). This variant has been reported in trans with pathogenic PMS2 variants in multiple families with constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 21376568, 16144131, 21204794). In separate analyses, this c.137G>T missense variant was identified in more than 10 probands with colon and/or endometrial cancer (PMID: 22577899, 16619239), and has been reported to segregate with colorectal and bladder cancer in a single family with suspected Lynch syndrome (PMID: 23709753). ClinVar contains an entry for this variant (Variation ID: 9245). Experimental studies have shown that this missense change significantly impairs the mismatch repair activity of PMS2 (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,Partners HealthCare Personalized Medicine RCV000076807 SCV000271259 pathogenic Lynch syndrome 2018-03-23 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, 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.
Illumina Clinical Services Laboratory,Illumina RCV000056324 SCV000469744 likely pathogenic Hereditary nonpolyposis colorectal cancer type 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 The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507649 SCV000604885 pathogenic none provided 2020-08-31 criteria provided, single submitter clinical testing The PMS2 c.137G>T;p.Ser46Ile variant has been 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 as pathogenic by multiple laboratories in ClinVar (Variation ID: 9245) and is found in the Latino population with an overall allele frequency of 0.03% (11/34312 alleles) in the Genome Aggregation Database. Several individuals with constitutional mismatch repair-deficiency carried this variant in trans to a second 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. 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. 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. Jackson CC et al. Café-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. Senter L et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008 Aug;135(2):419-28. Tomsic J et al. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013 Mar;83(3):238-43.
Counsyl RCV000056324 SCV000677739 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2015-05-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115657 SCV000686122 pathogenic Hereditary cancer-predisposing syndrome 2020-10-23 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 ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant significantly impairs the mismatch repair activity of PMS2 (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, 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 Hereditary nonpolyposis colorectal cancer type 4 2017-04-19 criteria provided, single submitter clinical testing
Mendelics RCV000076807 SCV000838198 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000056324 SCV000840051 pathogenic Hereditary nonpolyposis colorectal cancer type 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 Clinical Genomics Lab, 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 RCV000763592 SCV000894431 pathogenic Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 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 Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000200994 SCV001450303 likely pathogenic not provided 2016-02-05 criteria provided, single submitter clinical testing
OMIM RCV001267878 SCV000030047 pathogenic Mismatch repair cancer syndrome 4 2013-08-01 no assertion criteria provided literature only
OMIM RCV000056324 SCV000087493 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2013-08-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000009826 SCV000190470 pathogenic Turcot syndrome 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.

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