Refining the role of<i>pms2</i>in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants

Borràs, Ester; Pineda, Marta; Cadiñanos, Juan; Valle, Jesús Del; Brieger, Angela; Hinrichsen, Inga; Cabanillas, Rubén; Navarro, Matilde; Brunet, Joan; Sanjuán, Xavier; Musulén, Eva; Klift, Helen van der; Lázaro, Conxi; Plotz, Guido; Blanco, Ignacio; Capellà, Gabriel

doi:10.1136/jmedgenet-2012-101511

Cited by 48 publications

(44 citation statements)

References 55 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All laboratories aimed at avoiding interference by pseudogenes by applying different methods (Supplementary Table S1 online). Data on RNA splicing and transcript expression were available for approximately half of all mutations [13][14][15][16][17] The mutations were therefore classified into three genotype groups:…”

Section: Pms2 Mutationsmentioning

confidence: 99%

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

Suerink

Klift

Broeke

et al. 2016

Genetics in Medicine

View full text Add to dashboard Cite

A germ-line mutation in one of the mismatch repair (MMR) genes causes Lynch syndrome (LS), an autosomal dominant disorder characterized by the clustering of colorectal cancer (CRC) and endometrial cancer (EC) within affected families. Higher risks have been reported for other cancers such as ovarian and urothelial cell cancer. However, thus far only one study has confirmed these risks in PMS2 mutation carriers. 1The MMR proteins normally act together to repair mismatches that occur during cell replication. MSH2 and MSH6 form a heterodimer that recognizes base-base mismatches and insertion/deletion mispairs, whereas MLH1 and PMS2 form a heterodimer that supports initiated repair.2 A mutation can result in complete loss of protein or a protein with impaired function. Cancer risks associated with PMS2 are lower than those reported for MLH1 and MSH2. 1,3 Phenotypes resulting from germ-line MMR gene mutations vary both among and within families. 4 Interfamilial variance might be partly attributable to known genotype-phenotype Purpose: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.Methods: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally.Results: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC.Conclusions: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-oforigin effect.

show abstract

Section: Pms2 Mutationsmentioning

confidence: 99%

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

Suerink

Klift

Broeke

et al. 2016

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…The PMS2 c.538-3C>G minigene, tested in both HEK293 and HeLa cells, shows complete aberrant splicing, consisting of Δ6p_49nts and Δ6p_52nts (sequence chromatogram at right), a splice pattern different from the one reported by Borras et al. 2013, in patient RNA. PMS2 c.614A>C (p.Gln205Pro), and PMS2 c.687T>C (p.=), both tested only in HeLa, show a subtle difference in alternative expression (lacking Δ6) in comparison to the wild-type minigene allele (sequence chromatograms available on request).…”

Section: Resultsmentioning

confidence: 99%

“…2009; PMS2 c.538-3C>G and c.989-2A>G, Borras et al. 2013). Seventeen variants were located in the consensus splice site regions, including nine at the canonical −1, −2, +1, +2 positions.…”

Section: Methodsmentioning

confidence: 99%

Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses

Klift

Jansen

Steenstraten

et al. 2015

Molec Gen & Gen Med

View full text Add to dashboard Cite

A subset of DNA variants causes genetic disease through aberrant splicing. Experimental splicing assays, either RT-PCR analyses of patient RNA or functional splicing reporter minigene assays, are required to evaluate the molecular nature of the splice defect. Here, we present minigene assays performed for 17 variants in the consensus splice site regions, 14 exonic variants outside these regions, and two deep intronic variants, all in the DNA mismatch-repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, associated with Lynch syndrome. We also included two deep intronic variants in APC and PKD2. For one variant (MLH1 c.122A>G), our minigene assay and patient RNA analysis could not confirm the previously reported aberrant splicing. The aim of our study was to further investigate the concordance between minigene splicing assays and patient RNA analyses. For 30 variants results from patient RNA analyses were available, either performed by our laboratory or presented in literature. Some variants were deliberately included in this study because they resulted in multiple aberrant transcripts in patient RNA analysis, or caused a splice effect other than the prevalent exon skip. While both methods were completely concordant in the assessment of splice effects, four variants exhibited major differences in aberrant splice patterns. Based on the present and earlier studies, together showing an almost 100% concordance of minigene assays with patient RNA analyses, we discuss the weight given to minigene splicing assays in the current criteria proposed by InSiGHT for clinical classification of MMR variants.

show abstract

“…In another study, monoallelic PMS2 c.1A>G mutations were interpreted as pathogenic because of a lack of PMS2 protein staining in a patient with endometrial cancer diagnosed at 42 years of age (Borras et al. 2013). As described, there are several evidences for the pathogenicity of both MLH1 and PMS2 c.1A>G.…”

Section: Discussionmentioning

confidence: 99%

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Sjursen

McPhillips²,

Scott

et al. 2016

Molec Gen & Gen Med

View full text Add to dashboard Cite

BackgroundLynch syndrome, the most frequent hereditary colorectal cancer syndrome, is caused by defects in mismatch repair genes. Genetic testing is important in order to identify mutation carriers who can benefit from intensive surveillance programs. One of the challenges with genetic testing is the interpretation of pathogenicity of detected DNA variants. The aim of this study was to investigate all putative pathogenic variants tested for at the Division of Molecular Medicine, Pathology North, in Newcastle, Australia, to establish whether previous variant classification is in accordance with that recently performed in the InSiGHT collaboration.MethodsPrediction programs and available literature were used to classify new variants or variants without classification.ResultsWe identified 333 mutation positive families, in which 211 different putative pathogenic mismatch repair mutations were found. Most variants with an InSiGHT classification (141 out of 146) were in accordance with our classification. Five variants were discordant, of which one can definitively be reclassified according to the InSiGHT scheme as class 5. Sixty‐four variants had not been classified by InSiGHT, of whom 55 have not been previously reported.ConclusionIn conclusion, we found that our classifications were mostly in accordance with the InSiGHT scheme. In addition to already known MMR mutations, we have also presented 55 novel pathogenic or putative pathogenic mutations.

show abstract

Refining the role ofpms2in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants

Cited by 48 publications

References 55 publications

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Contact Info

Product

Resources

About