APC germline mutations in individuals being evaluated for familial adenomatous polyposis: A review of the mayo clinic experience with 1591 consecutive tests

Sarah E. Kerr, Cheryl B. Thomas, Stephen N Thibodeau, Matthew J. Ferber, Kevin C. Halling

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Consecutive cases (n = 1591) submitted for complete APC gene analysis during a 4-year period were reviewed. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43%, 42%, 9%, and 6% of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligation-dependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis.

Original languageEnglish (US)
Pages (from-to)31-43
Number of pages13
JournalJournal of Molecular Diagnostics
Volume15
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Adenomatous Polyposis Coli
Germ-Line Mutation
Frameshift Mutation
Nonsense Codon
Mutation
Multiplex Polymerase Chain Reaction
APC Genes
Adenomatous Polyps
Gene Duplication
Gene Deletion
Genetic Testing
Reflex
Electrophoresis
Colorectal Neoplasms
Gels
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Pathology and Forensic Medicine

Cite this

APC germline mutations in individuals being evaluated for familial adenomatous polyposis : A review of the mayo clinic experience with 1591 consecutive tests. / Kerr, Sarah E.; Thomas, Cheryl B.; Thibodeau, Stephen N; Ferber, Matthew J.; Halling, Kevin C.

In: Journal of Molecular Diagnostics, Vol. 15, No. 1, 01.2013, p. 31-43.

Research output: Contribution to journalArticle

@article{6aa20cb5a8a14fb1b7d10974f9c52302,
title = "APC germline mutations in individuals being evaluated for familial adenomatous polyposis: A review of the mayo clinic experience with 1591 consecutive tests",
abstract = "Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98{\%} of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Consecutive cases (n = 1591) submitted for complete APC gene analysis during a 4-year period were reviewed. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43{\%}, 42{\%}, 9{\%}, and 6{\%} of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligation-dependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis.",
author = "Kerr, {Sarah E.} and Thomas, {Cheryl B.} and Thibodeau, {Stephen N} and Ferber, {Matthew J.} and Halling, {Kevin C.}",
year = "2013",
month = "1",
doi = "10.1016/j.jmoldx.2012.07.005",
language = "English (US)",
volume = "15",
pages = "31--43",
journal = "Journal of Molecular Diagnostics",
issn = "1525-1578",
publisher = "Association of Molecular Pathology",
number = "1",

}

TY - JOUR

T1 - APC germline mutations in individuals being evaluated for familial adenomatous polyposis

T2 - A review of the mayo clinic experience with 1591 consecutive tests

AU - Kerr, Sarah E.

AU - Thomas, Cheryl B.

AU - Thibodeau, Stephen N

AU - Ferber, Matthew J.

AU - Halling, Kevin C.

PY - 2013/1

Y1 - 2013/1

N2 - Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Consecutive cases (n = 1591) submitted for complete APC gene analysis during a 4-year period were reviewed. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43%, 42%, 9%, and 6% of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligation-dependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis.

AB - Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Consecutive cases (n = 1591) submitted for complete APC gene analysis during a 4-year period were reviewed. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43%, 42%, 9%, and 6% of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligation-dependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis.

UR - http://www.scopus.com/inward/record.url?scp=84875443082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875443082&partnerID=8YFLogxK

U2 - 10.1016/j.jmoldx.2012.07.005

DO - 10.1016/j.jmoldx.2012.07.005

M3 - Article

C2 - 23159591

AN - SCOPUS:84875443082

VL - 15

SP - 31

EP - 43

JO - Journal of Molecular Diagnostics

JF - Journal of Molecular Diagnostics

SN - 1525-1578

IS - 1

ER -