Determining the frequency of de novo germline mutations in DNA mismatch repair genes

Aung K O Win, Mark A. Jenkins, Daniel D. Buchanan, Mark Clendenning, Joanne P. Young, Graham G. Giles, Jack Goldblatt, Barbara A. Leggett, John L. Hopper, Stephen N Thibodeau, Noralane Morey Lindor

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Abstract

Background: Carriers of a germline mutation in a DNA mismatch repair (MMR) gene-that is, persons with Lynch syndrome-have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Methods: Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Results: Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6. Conclusion: De novo MMR gene mutations are uncommon causes of Lynch syndrome.

Original languageEnglish (US)
Pages (from-to)530-534
Number of pages5
JournalJournal of Medical Genetics
Volume48
Issue number8
DOIs
StatePublished - Aug 2011

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DNA Mismatch Repair
Germ-Line Mutation
Mutation
Genes
Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Registries
Immunohistochemistry
Population
Gene Frequency
Colonic Neoplasms
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Win, A. K. O., Jenkins, M. A., Buchanan, D. D., Clendenning, M., Young, J. P., Giles, G. G., ... Lindor, N. M. (2011). Determining the frequency of de novo germline mutations in DNA mismatch repair genes. Journal of Medical Genetics, 48(8), 530-534. https://doi.org/10.1136/jmedgenet-2011-100082

Determining the frequency of de novo germline mutations in DNA mismatch repair genes. / Win, Aung K O; Jenkins, Mark A.; Buchanan, Daniel D.; Clendenning, Mark; Young, Joanne P.; Giles, Graham G.; Goldblatt, Jack; Leggett, Barbara A.; Hopper, John L.; Thibodeau, Stephen N; Lindor, Noralane Morey.

In: Journal of Medical Genetics, Vol. 48, No. 8, 08.2011, p. 530-534.

Research output: Contribution to journalArticle

Win, AKO, Jenkins, MA, Buchanan, DD, Clendenning, M, Young, JP, Giles, GG, Goldblatt, J, Leggett, BA, Hopper, JL, Thibodeau, SN & Lindor, NM 2011, 'Determining the frequency of de novo germline mutations in DNA mismatch repair genes', Journal of Medical Genetics, vol. 48, no. 8, pp. 530-534. https://doi.org/10.1136/jmedgenet-2011-100082
Win, Aung K O ; Jenkins, Mark A. ; Buchanan, Daniel D. ; Clendenning, Mark ; Young, Joanne P. ; Giles, Graham G. ; Goldblatt, Jack ; Leggett, Barbara A. ; Hopper, John L. ; Thibodeau, Stephen N ; Lindor, Noralane Morey. / Determining the frequency of de novo germline mutations in DNA mismatch repair genes. In: Journal of Medical Genetics. 2011 ; Vol. 48, No. 8. pp. 530-534.
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abstract = "Background: Carriers of a germline mutation in a DNA mismatch repair (MMR) gene-that is, persons with Lynch syndrome-have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Methods: Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Results: Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3{\%}, 95{\%} CI 0.9{\%} to 5.0{\%}) were confirmed as de novo, and the remaining 255 (97.7{\%}, 95{\%} CI 95.0{\%} to 99.1{\%}) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5{\%}, 95{\%} CI 0.3{\%} to 4.5{\%}) and three were population based probands (5.1{\%}, 95{\%} CI 1.2{\%} to 14.5{\%}). Two were in MLH1, three in MSH2, and one in MSH6. Conclusion: De novo MMR gene mutations are uncommon causes of Lynch syndrome.",
author = "Win, {Aung K O} and Jenkins, {Mark A.} and Buchanan, {Daniel D.} and Mark Clendenning and Young, {Joanne P.} and Giles, {Graham G.} and Jack Goldblatt and Leggett, {Barbara A.} and Hopper, {John L.} and Thibodeau, {Stephen N} and Lindor, {Noralane Morey}",
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T1 - Determining the frequency of de novo germline mutations in DNA mismatch repair genes

AU - Win, Aung K O

AU - Jenkins, Mark A.

AU - Buchanan, Daniel D.

AU - Clendenning, Mark

AU - Young, Joanne P.

AU - Giles, Graham G.

AU - Goldblatt, Jack

AU - Leggett, Barbara A.

AU - Hopper, John L.

AU - Thibodeau, Stephen N

AU - Lindor, Noralane Morey

PY - 2011/8

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N2 - Background: Carriers of a germline mutation in a DNA mismatch repair (MMR) gene-that is, persons with Lynch syndrome-have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Methods: Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Results: Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6. Conclusion: De novo MMR gene mutations are uncommon causes of Lynch syndrome.

AB - Background: Carriers of a germline mutation in a DNA mismatch repair (MMR) gene-that is, persons with Lynch syndrome-have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Methods: Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Results: Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6. Conclusion: De novo MMR gene mutations are uncommon causes of Lynch syndrome.

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