A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue

被引:9
|
作者
Klancar, Gasper [1 ]
Blatnik, Ana [2 ]
Dragos, Vita Setrajcic [1 ]
Vogric, Vesna [1 ]
Stegel, Vida [1 ]
Blatnik, Olga [3 ]
Drev, Primoz [3 ]
Gazic, Barbara [3 ]
Krajc, Mateja [2 ]
Novakovic, Srdjan [1 ]
机构
[1] Inst Oncol Ljubljana, Dept Mol Diagnost, SI-1000 Ljubljana, Slovenia
[2] Inst Oncol Ljubljana, Canc Genet Clin, SI-1000 Ljubljana, Slovenia
[3] Inst Oncol Ljubljana, Dept Pathol, SI-1000 Ljubljana, Slovenia
关键词
Lynch syndrome; MMR; novel MLH1 variant; segregation analysis; isolated PMS2 loss; MISMATCH REPAIR; MICROSATELLITE INSTABILITY; FUNCTIONAL-ANALYSIS; MUTATION; CANCER; UPDATE; IMMUNOHISTOCHEMISTRY; ENDOMETRIAL; DIAGNOSTICS; MECHANISMS;
D O I
10.3390/genes11030325
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel MLH1 in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in MLH1. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel MLH1 variant as likely pathogenic, we confirmed the LS in this family.
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页数:15
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共 42 条
  • [1] Association of novel germline MLH1 in-frame deletion with uncommon isolated PMS2 loss in tumor tissue
    Klancar, Gasper
    Blatnik, Ana
    Dragos, Vita Setrajcic
    Vogric, Vesna
    Stegel, Vida
    Blatnik, Olga
    Drev, Primoz
    Gazic, Barbara
    Krajc, Mateja
    Novakovic, Srdjan
    [J]. EUROPEAN JOURNAL OF HUMAN GENETICS, 2022, 30 (SUPPL 1) : 417 - 417
  • [2] Germline Mutations in MLH1 Leading to Isolated Loss of PMS2 Expression in Lynch Syndrome: Implications for Diagnostics in the Clinic
    Silva, Felipe C. C.
    Torrezan, Giovana Tardin
    Ferreira, Jose R. O.
    Oliveira, Ligia P.
    Begnami, Maria D. F. S.
    Aguiar Junior, Samuel
    Carraro, Dirce M.
    [J]. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2017, 41 (06) : 861 - 864
  • [3] Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?
    João Lobo
    Carla Pinto
    Micaela Freitas
    Manuela Pinheiro
    Rámon Vizcaino
    Esther Oliva
    Manuel R. Teixeira
    Carmen Jerónimo
    Carla Bartosch
    [J]. Virchows Archiv, 2017, 470 : 347 - 352
  • [4] Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?
    Lobo, Joao
    Pinto, Carla
    Freitas, Micaela
    Pinheiro, Manuela
    Vizcaino, Ramon
    Oliva, Esther
    Teixeira, Manuel R.
    Jeronimo, Carmen
    Bartosch, Carla
    [J]. VIRCHOWS ARCHIV, 2017, 470 (03) : 347 - 352
  • [5] Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression
    Dudley, Beth
    Brand, Randall E.
    Thull, Darcy
    Bahary, Nathan
    Nikiforova, Marina N.
    Pai, Reetesh K.
    [J]. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2015, 39 (08) : 1114 - 1120
  • [6] MLH1, PMS2 And MSH6 Loss; Sporadic, Germline or Both?
    Zia, Shereen
    Hein, Ashley
    Krishnan, Ramakrishnan
    Dumur, Catherine
    Khoury, Joseph
    Pradhan, Dinesh
    [J]. LABORATORY INVESTIGATION, 2024, 104 (03) : S869 - S870
  • [7] Nine novel pathogenic germline mutations in MLH1, MSH2, MSH6 and PMS2 in families with Lynch syndrome
    Rahner, Nils
    Friedrichs, Nicolaus
    Wehner, Maria
    Steinke, Verena
    Aretz, Stefan
    Friedl, Waltraut
    Buettner, Reinhard
    Mangold, Elisabeth
    Propping, Peter
    Walldorf, Constanze
    [J]. ACTA ONCOLOGICA, 2007, 46 (06) : 763 - 769
  • [8] Ovarian uveal melanoma metastasis showing MLH1/PMS2 protein loss in a patient with Lynch Syndrome
    Lobo, J.
    Pinto, C.
    Freitas, M.
    Vieira, R.
    Machado, B.
    Pinheiro, M.
    Vizcaino, R.
    Oliva, E.
    Teixeira, M. R.
    Jeronimo, C.
    Bartosch, C.
    [J]. VIRCHOWS ARCHIV, 2016, 469 : S101 - S101
  • [9] Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort
    Rosty, Christophe
    Clendenning, Mark
    Walsh, Michael D.
    Eriksen, Stine V.
    Southey, Melissa C.
    Winship, Ingrid M.
    Macrae, Finlay A.
    Boussioutas, Alex
    Poplawski, Nicola K.
    Parry, Susan
    Arnold, Julie
    Young, Joanne P.
    Casey, Graham
    Haile, Robert W.
    Gallinger, Steven
    Le Marchand, Loic
    Newcomb, Polly A.
    Potter, John D.
    DeRycke, Melissa
    Lindor, Noralane M.
    Thibodeau, Stephen N.
    Baron, John A.
    Win, Aung Ko
    Hopper, John L.
    Jenkins, Mark A.
    Buchanan, Daniel D.
    [J]. BMJ OPEN, 2016, 6 (02):
  • [10] Isolated Loss of PMS2 Immunohistochemical Expression is Frequently Caused by Heterogenous MLH1 Promoter Hypermethylation in Lynch Syndrome Screening for Endometrial Cancer Patients
    Kato, Aya
    Sato, Naoki
    Sugawara, Tae
    Takahashi, Kazue
    Kito, Masahiko
    Makino, Kenichi
    Sato, Toshiharu
    Shimizu, Dai
    Shirasawa, Hiromistu
    Miura, Hiroshi
    Sato, Wataru
    Kumazawa, Yukiyo
    Sato, Akira
    Kumagai, Jin
    Terada, Yukihiro
    [J]. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2016, 40 (06) : 770 - 776