The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes

Smith, Miriam J.; Urquhart, Jill; Harkness, Elaine; Miles, Emma; Bowers, Naomi L.; Byers, Helen; Bulman, Michael P.; Gokhale, Carolyn; Wallace, Andrew; Newman, William G.; Evans, D. Gareth

doi:10.1002/humu.22938

Cited by 56 publications

(55 citation statements)

References 63 publications

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“…1b). Our data support evidence on a significant contribution from whole-exon deletions in MSH2 and PMS2, and demonstrate a higher rate of large deletions than previously reported in MLH1 (28,29). Of the 201 sequence variants reported, 137 are available in the InSiGhT database, whereas 64 have not previously been reported.…”

Section: Discussionsupporting

confidence: 90%

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

et al. 2016

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Abstract. Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6.Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.

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Section: Discussionsupporting

confidence: 90%

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

et al. 2016

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“…Deletions of CPGs with substantial childhood-onset risks such as SMARCB1 (malignant rhabdoid tumour) and TP53 (brain and sarcoma) also appear to be not infrequent and there is no evidence these deletions are less penetrant than point mutations 27. On the other hand, we also detected an inherited deletion encompassing BMPR1A (P005), where there was no family history of polyposis.…”

Section: Discussionmentioning

confidence: 68%

“…Indeed, recent analysis of a range of CPGs showed that large deletions including whole gene deletions were associated with fairly typical cancer predisposition compared with point mutations 27. Deletions of CPGs with substantial childhood-onset risks such as SMARCB1 (malignant rhabdoid tumour) and TP53 (brain and sarcoma) also appear to be not infrequent and there is no evidence these deletions are less penetrant than point mutations 27.…”

Section: Discussionmentioning

confidence: 99%

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing

et al. 2017

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Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

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“…Deletions and duplications of whole exons, termed ‘exon copy number variants’ or ‘exon CNVs’, are an important class of clinically relevant gene mutations 4 . Accurate exon CNV detection has proved difficult in targeted NGS data, particularly if only a single exon is affected 5 .…”

Section: Introductionmentioning

confidence: 99%

The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data

Mahamdallie¹,

Ruark²,

Yost³

et al. 2017

Wellcome Open Res

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Detection of deletions and duplications of whole exons (exon CNVs) is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS) data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly-available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA) under the accession number EGAS00001002428.

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The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes

Cited by 56 publications

References 63 publications

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing

The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data

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