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

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@article{e81338d18f6d4b4e8ada3aaf68bafc94,
title = "A rare missense variant in APC interrupts splicing and causes AFAP in two Danish families",
abstract = "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.",
keywords = "Adenocarcinoma, APC, Colorectal cancer, Missense variant, Polyposis, Splicing",
author = "Malene Djursby and Karin Wadt and Frederiksen, {Jane H{\"u}bertz} and Madsen, {Majbritt Busk} and Berchtold, {Lukas Adrian} and Hasselby, {Jane Preuss} and Willemoe, {Gro Linno} and Hansen, {Thomas V O} and Anne-Marie Gerdes",
note = "{\circledC} The Author(s) 2020.",
year = "2020",
month = "4",
day = "7",
doi = "10.1186/s13053-020-00140-3",
language = "English",
volume = "18",
pages = "1--6",
journal = "Hereditary Cancer in Clinical Practice",
issn = "1731-2302",
publisher = "BioMed Central Ltd",

}

RIS

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

VL - 18

SP - 1

EP - 6

JO - Hereditary Cancer in Clinical Practice

JF - Hereditary Cancer in Clinical Practice

SN - 1731-2302

M1 - 8

ER -

ID: 59671958