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
N1 - © The Author(s) 2020.
PY - 2020/4/7
Y1 - 2020/4/7
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
UR - http://www.scopus.com/inward/record.url?scp=85083112468&partnerID=8YFLogxK
U2 - 10.1186/s13053-020-00140-3
DO - 10.1186/s13053-020-00140-3
M3 - Journal article
C2 - 32292534
SN - 1731-2302
VL - 18
SP - 1
EP - 6
JO - Hereditary Cancer in Clinical Practice
JF - Hereditary Cancer in Clinical Practice
IS - 1
M1 - 8
ER -