TY - JOUR

T1 - A rare missense variant in APC interrupts splicing and causes AFAP in two Danish families

AU - Djursby, Malene

AU - Wadt, Karin

AU - Frederiksen, Jane Hübertz

AU - Madsen, Majbritt Busk

AU - Berchtold, Lukas Adrian

AU - Hasselby, Jane Preuss

AU - Willemoe, Gro Linno

AU - Hansen, Thomas V.O.

AU - Gerdes, Anne Marie

PY - 2020

Y1 - 2020

N2 - Background: We report the first case of a missense variant in the APC gene that interrupts splicing by creating a new cryptic acceptor site. The variant, c.289G>A, p.(Gly97Arg), is located in exon 3, and qualitative and semi-quantitative RNA splicing analysis reveal that the variant results in skipping of the last 70 nucleotides of the exon, which leads to the introduction of a frameshift and a premature stop codon. Case presentation: The variant was detected in two, apparently unrelated, Danish families with an accumulation of colorectal cancers, colonic adenomas and other cancers. The families both have an attenuated familial adenomatous polyposis phenotype, which is consistent with the association of pathogenic variants in the 5′ end of the gene. One variant-carrier also had Caroli Disease and a Caroli Disease associated hepatic mucinous cystadenocarcinoma. This is the first description of a person with both Caroli Disease and a pathogenic APC variant, and although the APC variant is not known to be connected to the development of the hepatic malformations in Caroli Disease, it remains unclear whether the variant could have contributed to the carcinogenesis of the liver tumour. Conclusions: Based on functional and co-segregation data we classify the APC c.289G>A, p.(Gly97Arg) variant as pathogenic (class 5). Our findings emphasize the importance of a functional evaluation of missense variants although located far from the exon-intron boundaries.

AB - Background: We report the first case of a missense variant in the APC gene that interrupts splicing by creating a new cryptic acceptor site. The variant, c.289G>A, p.(Gly97Arg), is located in exon 3, and qualitative and semi-quantitative RNA splicing analysis reveal that the variant results in skipping of the last 70 nucleotides of the exon, which leads to the introduction of a frameshift and a premature stop codon. Case presentation: The variant was detected in two, apparently unrelated, Danish families with an accumulation of colorectal cancers, colonic adenomas and other cancers. The families both have an attenuated familial adenomatous polyposis phenotype, which is consistent with the association of pathogenic variants in the 5′ end of the gene. One variant-carrier also had Caroli Disease and a Caroli Disease associated hepatic mucinous cystadenocarcinoma. This is the first description of a person with both Caroli Disease and a pathogenic APC variant, and although the APC variant is not known to be connected to the development of the hepatic malformations in Caroli Disease, it remains unclear whether the variant could have contributed to the carcinogenesis of the liver tumour. Conclusions: Based on functional and co-segregation data we classify the APC c.289G>A, p.(Gly97Arg) variant as pathogenic (class 5). Our findings emphasize the importance of a functional evaluation of missense variants although located far from the exon-intron boundaries.

KW - Adenocarcinoma

KW - APC

KW - Colorectal cancer

KW - Missense variant

KW - Polyposis

KW - Splicing

U2 - 10.1186/s13053-020-00140-3

DO - 10.1186/s13053-020-00140-3

M3 - Journal article

C2 - 32292534

AN - SCOPUS:85083112468

VL - 18

JO - Hereditary Cancer in Clinical Practice

JF - Hereditary Cancer in Clinical Practice

SN - 1731-2302

IS - 1

M1 - 8

ER -