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Mutation-Negative Lynch Syndrome

MedGen UID:
1651000
•Concept ID:
C4725945
•
Disease or Syndrome
Synonym: Lynch-Like Syndrome

Definition

A finding of Lynch syndrome in which one is identified as having a ""non-sporadic"" DNA mismatch repair (MMR) deficient premalignant lesion or ""non-sporadic"" MMR deficient malignant tumor, but germline MMR genetic testing did not demonstrate a recognized pathogenic mutation in the genes responsible for DNA mismatch repair. [from NCI]

Professional guidelines

PubMed

Colon cancer screening practices after genetic counseling and testing for hereditary nonpolyposis colorectal cancer.
Hadley DW, Jenkins JF, Dimond E, de Carvalho M, Kirsch I, Palmer CG
J Clin Oncol 2004 Jan 1;22(1):39-44. doi: 10.1200/JCO.2004.06.128. PMID: 14701766
Genetic testing for polyposis: practical and ethical aspects.
Järvinen HJ
Gut 2003 May;52 Suppl 2(Suppl 2):ii19-22. doi: 10.1136/gut.52.suppl_2.ii19. PMID: 12651878Free PMC Article
Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer.
Heinimann K, Scott RJ, Buerstedde JM, Weber W, Siebold K, Attenhofer M, Müller H, Dobbie Z
Cancer 1999 Jun 15;85(12):2512-8. doi: 10.1002/(sici)1097-0142(19990615)85:12<2512::aid-cncr4>3.0.co;2-g. PMID: 10375096

Recent clinical studies

Etiology

Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG
JAMA Oncol 2015 Apr;1(1):23-32. doi: 10.1001/jamaoncol.2014.168. PMID: 26182300
Causes of death of mutation carriers in Finnish Lynch syndrome families.
Pylvänäinen K, Lehtinen T, Kellokumpu I, Järvinen H, Mecklin JP
Fam Cancer 2012 Sep;11(3):467-71. doi: 10.1007/s10689-012-9537-3. PMID: 22684865
Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors.
Rahner N, Brockschmidt FF, Steinke V, Kahl P, Becker T, Vasen HF, Wijnen JT, Tops CJ, Holinski-Feder E, Ligtenberg MJ, Spruijt L, Görgens H, Stemmler S, Kloor M, Dietmaier W; Dutch Cancer Genetics Group, Schumacher J, Nöthen MM, Propping P
Fam Cancer 2012 Mar;11(1):19-26. doi: 10.1007/s10689-011-9489-z. PMID: 22086303
Large genomic rearrangements and germline epimutations in Lynch syndrome.
Gylling A, Ridanpää M, Vierimaa O, Aittomäki K, Avela K, Kääriäinen H, Laivuori H, Pöyhönen M, Sallinen SL, Wallgren-Pettersson C, Järvinen HJ, Mecklin JP, Peltomäki P
Int J Cancer 2009 May 15;124(10):2333-40. doi: 10.1002/ijc.24230. PMID: 19173287
Histology of prophylactically removed ovaries from BRCA1 and BRCA2 mutation carriers compared with noncarriers in hereditary breast ovarian cancer syndrome kindreds.
Casey MJ, Bewtra C, Hoehne LL, Tatpati AD, Lynch HT, Watson P
Gynecol Oncol 2000 Sep;78(3 Pt 1):278-87. doi: 10.1006/gyno.2000.5861. PMID: 10985881

Diagnosis

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies.
Plowman JN, Matoy EJ, Uppala LV, Draves SB, Watson CJ, Sefranek BA, Stacey ML, Anderson SP, Belshan MA, Blue EE, Huff CD, Fu Y, Stessman HAF
HGG Adv 2024 Jul 18;5(3):100306. Epub 2024 May 10 doi: 10.1016/j.xhgg.2024.100306. PMID: 38734904Free PMC Article
Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG
JAMA Oncol 2015 Apr;1(1):23-32. doi: 10.1001/jamaoncol.2014.168. PMID: 26182300
Causes of death of mutation carriers in Finnish Lynch syndrome families.
Pylvänäinen K, Lehtinen T, Kellokumpu I, Järvinen H, Mecklin JP
Fam Cancer 2012 Sep;11(3):467-71. doi: 10.1007/s10689-012-9537-3. PMID: 22684865
Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members.
Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, Peltomäki P, Aaltonen LA, Mecklin JP
J Clin Oncol 2009 Oct 1;27(28):4793-7. Epub 2009 Aug 31 doi: 10.1200/JCO.2009.23.7784. PMID: 19720893
Large genomic rearrangements and germline epimutations in Lynch syndrome.
Gylling A, Ridanpää M, Vierimaa O, Aittomäki K, Avela K, Kääriäinen H, Laivuori H, Pöyhönen M, Sallinen SL, Wallgren-Pettersson C, Järvinen HJ, Mecklin JP, Peltomäki P
Int J Cancer 2009 May 15;124(10):2333-40. doi: 10.1002/ijc.24230. PMID: 19173287

Therapy

Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.
Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB
J Med Genet 2012 Mar;49(3):151-7. doi: 10.1136/jmedgenet-2011-100714. PMID: 22368298
A protocol for genetic evaluation of patients with multiple colorectal adenomas and without evidence of APC gene mutation.
Rosner G, Rozen P, Bercovich D, Shochat C, Solar I, Strul H, Kariv R, Halpern Z
Isr Med Assoc J 2010 Sep;12(9):549-53. PMID: 21287799

Prognosis

Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes.
Kayser K, Degenhardt F, Holzapfel S, Horpaopan S, Peters S, Spier I, Morak M, Vangala D, Rahner N, von Knebel-Doeberitz M, Schackert HK, Engel C, Büttner R, Wijnen J, Doerks T, Bork P, Moebus S, Herms S, Fischer S, Hoffmann P, Aretz S, Steinke-Lange V
Int J Cancer 2018 Dec 1;143(11):2800-2813. Epub 2018 Oct 3 doi: 10.1002/ijc.31725. PMID: 29987844
Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG
JAMA Oncol 2015 Apr;1(1):23-32. doi: 10.1001/jamaoncol.2014.168. PMID: 26182300
Causes of death of mutation carriers in Finnish Lynch syndrome families.
Pylvänäinen K, Lehtinen T, Kellokumpu I, Järvinen H, Mecklin JP
Fam Cancer 2012 Sep;11(3):467-71. doi: 10.1007/s10689-012-9537-3. PMID: 22684865
Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.
Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB
J Med Genet 2012 Mar;49(3):151-7. doi: 10.1136/jmedgenet-2011-100714. PMID: 22368298
Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors.
Rahner N, Brockschmidt FF, Steinke V, Kahl P, Becker T, Vasen HF, Wijnen JT, Tops CJ, Holinski-Feder E, Ligtenberg MJ, Spruijt L, Görgens H, Stemmler S, Kloor M, Dietmaier W; Dutch Cancer Genetics Group, Schumacher J, Nöthen MM, Propping P
Fam Cancer 2012 Mar;11(1):19-26. doi: 10.1007/s10689-011-9489-z. PMID: 22086303

Clinical prediction guides

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies.
Plowman JN, Matoy EJ, Uppala LV, Draves SB, Watson CJ, Sefranek BA, Stacey ML, Anderson SP, Belshan MA, Blue EE, Huff CD, Fu Y, Stessman HAF
HGG Adv 2024 Jul 18;5(3):100306. Epub 2024 May 10 doi: 10.1016/j.xhgg.2024.100306. PMID: 38734904Free PMC Article
Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes.
Kayser K, Degenhardt F, Holzapfel S, Horpaopan S, Peters S, Spier I, Morak M, Vangala D, Rahner N, von Knebel-Doeberitz M, Schackert HK, Engel C, Büttner R, Wijnen J, Doerks T, Bork P, Moebus S, Herms S, Fischer S, Hoffmann P, Aretz S, Steinke-Lange V
Int J Cancer 2018 Dec 1;143(11):2800-2813. Epub 2018 Oct 3 doi: 10.1002/ijc.31725. PMID: 29987844
Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG
JAMA Oncol 2015 Apr;1(1):23-32. doi: 10.1001/jamaoncol.2014.168. PMID: 26182300
Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.
Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB
J Med Genet 2012 Mar;49(3):151-7. doi: 10.1136/jmedgenet-2011-100714. PMID: 22368298
Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors.
Rahner N, Brockschmidt FF, Steinke V, Kahl P, Becker T, Vasen HF, Wijnen JT, Tops CJ, Holinski-Feder E, Ligtenberg MJ, Spruijt L, Görgens H, Stemmler S, Kloor M, Dietmaier W; Dutch Cancer Genetics Group, Schumacher J, Nöthen MM, Propping P
Fam Cancer 2012 Mar;11(1):19-26. doi: 10.1007/s10689-011-9489-z. PMID: 22086303

Recent systematic reviews

Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.
Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB
J Med Genet 2012 Mar;49(3):151-7. doi: 10.1136/jmedgenet-2011-100714. PMID: 22368298

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