A nonsense mutation in exon 8 of the <i>APC</i> gene (Arg283Ter) causes clinically variable FAP in a Malaysian Chinese family

Zeriouh, Mohamed; Ahmad, Rahimah; Yoke, Ng Sau; Zakaria, Zubaidah; Ahmad, Harun; Yew, Tong Hung

doi:10.1111/j.1349-7006.2003.tb01509.x

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…It is also interesting to note that in our study, one family member (III4), aged 32 years, was reported to be asymptomatic but was an heterozygous carrier for the H672Qfs X5 mutation. Such instances have been reported and represent one of the main challenges in genotypephenotype correlation in FAP studies [8,16]. The phenotypic variations within families (intra-family) or between groups of individuals with the same germline mutation (inter-family) suggest that modifier genes, epigenetic mechanisms or environmental factors could modulate the FAP phenotype.…”

Section: Resultsmentioning

confidence: 95%

A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP

et al. 2011

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Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which typically presents with colorectal cancer in early adult life, secondary to extensive adenomatous polyps of the colon. In addition to the colonic manifestations, the syndrome presents several extracolonic features including, congenital hypertrophy of the retinal pigment, osteomata and desmoid tumors. In this study, we aimed to investigate the clinical and genetic features in a Tunisian family with FAP. Sequence of the APC gene (Adenomatous Polyposis Coli) revealed a novel mutation (c.2016-2017 del TA) in exon 15, present in all affected individuals in an heterozygous state. The frameshift mutation generates a premature stop codon at amino acid 677 of the APC protein (p. H672Qfs X5). The unaffected family members did not harbor this mutation, however, a first degree relative of the patient aged of 32-year-old was phenotypically normal but carries the c.2016-2017 del TA mutation. This discrepancy can be explained by the effect of modifier gene which can affect the expressivity of the disease.

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Section: Resultsmentioning

confidence: 95%

A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP

et al. 2011

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“…Following DNA sequencing of APC and MUTYH, micromutations were analyzed using Mutation Surveyor ( Table I ). For APC, four disease-associated pathogenic alterations (Lys1061LysfsTer2, Glu1309AspfsTer4, Arg283Ter and Ser1196Ter) were identified, which had been previously reported to be pathogenic mutations ( 31 – 33 , 13 ). In addition to the pathogenic mutations mentioned above, seven missense mutations (Ser784Thr, Ile880Leu, Arg1171Gly, Ile1259Leu, Asp1519Glu, Glu1552Val and Pro2216Thr), five synonymous substitutions (Tyr486Tyr, Tyr1493Tyr, Gly1678Gly, Ser1756Ser and Pro1960Pro) and three intronic mutations (c.220+35T>A, c.645+129A>C and c.1548+133C>A) were identified.…”

Section: Resultsmentioning

confidence: 97%

Synonymous mutation adenomatous polyposis coliΔ486s affects exon splicing and may predispose patients to adenomatous polyposis coli/mutY DNA glycosylase mutation‑negative familial adenomatous polyposis

et al. 2018

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Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer. Recent advances in genetics have indicated that the majority of patients with FAP carry germline mutations of the adenomatous polyposis coli (APC) and mutY DNA glycosylase (MUTYH) genes. However, a large subset of families with a history of FAP have undetectable pathogenic alterations, termed APC/MUTYH mutation-negative FAP. To investigate the germline mutations in the APC and MUTYH genes in Chinese patients with FAP, 13 unrelated patients were enrolled. Through genetic sequencing, four known pathogenic alterations (Lys1061LysfsTer2, Glu1309AspfsTer4, Arg283Ter and Ser1196Ter) of APC and two novel disease-associated pathogenic mutations (Tyr152Ter and Ter522Gly) in MUTYH were identified in six individuals. For samples that did not present with pathogenic alterations, the functional effects of missense, synonymous and intronic mutations were analyzed using bioinformatics tools and databases. Bioinformatics prediction suggested that the synonymous mutation Tyr486Tyr in APC (APC∆486s) was likely a disease-causing polymorphism and may have induced the exon skipping of APC. A hybrid mini-gene assay was performed, which confirmed that the synonymous single nucleotide polymorphism APC∆486s induced major splicing defects with skipping of exon 12 in APC. The data of the present study suggested that the synonymous polymorphism APC∆486s was a potential pathogenic alteration that predisposed APC/MUTYH mutation-negative patients to FAP.

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“…This variant has been reported in 15 probands, meeting eight phenotype points, and in 50 probands with FAP not otherwise specified, meeting more than 16 phenotype points in total. It has been reported to segregate with FAP in five meioses from one family and in 31 members from one large FAP family ( Mohamed et al, 2003 ). In summary, this variant meets the criteria to be classified as pathogenic for FAP based on the ACMG/AMP criteria applied.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel CNV at the APC gene in a Chinese family with familial adenomatous polyposis

Li¹,

He²,

Gong³

et al. 2023

Front. Mol. Biosci.

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Introduction: Familial adenomatous polyposis (FAP) is the second most commonly inherited colorectal cancer (CRC) predisposition caused by germline mutations within the adenomatous polyposis coli (APC) gene. The molecular defects and clinical manifestations of two FAP families were analyzed, and individual prevention strategies suitable for mutation carriers in different families were proposed.Methods and results: The pathogenic gene mutations were identified among the two families using whole-exome sequencing and verified with Sanger sequencing or quantitative polymerase chain reaction (qPCR). One novel (GRCh37:Chr5: 112145676–112174368, del, 28,692 bp) and a known (c.C847T:p.R283X) mutation in the APC gene were pathogenic mutations for FAP, according to the sequencing data and tumorigenesis pattern among the family members. The two mutations led to a premature translational stop signal, synthesizing an absent or disrupted protein product.Conclusion: Our findings expand the known germline mutation spectrum of the APC gene among the Chinese population. This reaffirms the importance of genetic testing in FAP. Genetic consultation and regular follow-ups are necessary for the individualized treatment of cancer-afflicted families with APC expression deficiency. Additional work is required to develop safe and effective chemotherapy and immunotherapy for FAP based on the mutation type.

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A nonsense mutation in exon 8 of the APC gene (Arg283Ter) causes clinically variable FAP in a Malaysian Chinese family

Cited by 6 publications

References 20 publications

A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP

A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP

Synonymous mutation adenomatous polyposis coliΔ486s affects exon splicing and may predispose patients to adenomatous polyposis coli/mutY DNA glycosylase mutation‑negative familial adenomatous polyposis

Identification of a novel CNV at the APC gene in a Chinese family with familial adenomatous polyposis

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