Identification of an APC Variant in a Patient with Clinical Attenuated Familial Adenomatous Polyposis

Abstract

Introduction. The objective of this case report is to discuss an unclassified germline variant of the adenomatous polyposis coli (APC) gene identified in an older patient with attenuated familial adenomatous polyposis syndrome (AFAP). Methods. We present a case report of a 66-year-old man diagnosed with AFAP. Colonoscopy found multiple polyps and invasive adenocarcinoma arising in the transverse colon. Samples were tested for mutations in the APC gene. Results. DNA sequencing of germline DNA identified a cytosine (C) to thymine (T) transition at nucleotide 1240, heterozygous. The C to T transition at codon 414 is predicted to convert an arginine residue to a cysteine that is possibly pathogenic. Analysis of the patient's colon tumor DNA indicated that the tumor had lost the mutant variant allele and retained only the normal allele, suggesting that the variant may not be significant. Conclusions. The p.R414C variant has been described previously as a germline mutation of probable pathogenicity. This substitution should be considered an unclassified variant and possibly not pathogenic. These findings support the need for further genetic testing of tissue, as well as for developing a mechanism for testing all variants, as this could significantly impact the lives of patients and their family members.

Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations

“…More recently, this variant was reported in a patient with attenuated FAP. However, in this case, the tumor had lost the allele carrying the p.Arg414Cys mutation questioning its pathogenicity . In our patient, though, the p.Arg414Cys mutation was also present in the tumor and in addition a second truncating mutation was identified, indicating that it may indeed be associated with aFAP (Supporting Information Table S2).…”

“…These included 2 small frameshift deletions or insertions, 1 nonsense mutation, 21 missense and 3 splice site mutations. Four variants ( APC : p.Arg414Cys, MLH1 : p.Gly67Arg, MSH6 : p.Tyr977* and p.Asp1171Glufs*5) were previously published as pathogenic, whereat the APC : p.Arg414Cys mutation is more recently reassessed as an unclassified variant . 8 variants have been already reported by the InSiGHT Colon Cancer Gene Variant Database for MMR and other colon cancer susceptibility genes hosted by the Leiden Open Variation Database (LOVD) .…”

Manifestaciones maxilofaciales en una familia chilena con adenomatosis poliposa familiar

“…En la familia chilena estudiada, la probando (III.1) presentó un odontoma compuesto; el sujeto III.5 anomalías de morfología de las piezas 7 y 10; y presencia de calcificaciones intracamerales en molares de paciente III.1 y III.5. En la familia estudiada, tanto el sujeto III.2, 46 años, que presentó osteomas, comoel sujeto III.1, 47 años,que presentó un odontoma compuesto, no asistieron a la evaluación por gastroenterólogo para realización de colonoscopía y evidenciar presencia de poliposis colónica en el tiempo de duración del estudio, sin confirmar el diagnóstico de PAF.A pesar de la edad de los pacientes (46 y 47 años) y antecedentes familiares de PAF, es importante realizar el examen intestinal para descartar la existencia de PAF atenuada que tiene un curso más leve que la PAF clásica con el desarrollo de menos número de pólipos y desarrollo tardío en la edad de cáncer colorrectal (4,6) .…”

“…El criterio clínico para diagnosticar la forma clásica de PAF es el desarrollo de 100 o más pólipos adenomatosos colorrectales siendo la mayoría en pacientes menores de cuarenta años. Los pacientes con este síndrome progresarán a cáncer de colon casi en el 100% de los casos si no son tratados (2)(3)(4) .…”

“…Los dentistas deben ser conscientes y conocer las anomalías maxilofaciales asociadas al SG ya que pueden desempeñar un papel importante en el diagnóstico precoz de este síndrome (1,4) .…”