title: Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency.
abstract: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare autosomal recessive predisposition to colorectal polyposis and other malignancies, often childhood-onset, that is caused by biallelic inheritance of mutations in the same mismatch repair gene. Here, we describe a patient with a clinical diagnosis of CMMRD based on colorectal polyposis and young-onset endometrial cancer who was identified to have two alterations in trans in PMS2: one known pathogenic mutation (c.1831insA; p.Ile611Asnfs*2) and one novel variant of uncertain significance (c.505C>G; p.Arg169Glu), a missense alteration. We describe the clinical and molecular features in the patient harboring this novel alteration c.505C>G, who meets clinical criteria for CMMRD and exhibits molecular evidence supporting a diagnosis of CMMRD. Although experimental validation is needed to confirm its pathogenicity, PMS2 c.505C>G likely has functional consequences that contributes to our patient's phenotype based on the patient's clinical presentation, tumor studies, and bioinformatics analysis.
authors.affiliation: Clinical Cancer Genetics Program, UT MD Anderson Center, Unit 1354, 1155 Pressler St., Houston, TX, 77030, USA.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Mork
authors.affiliation: Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Unit 1360, P.O. Box 301439, Houston, TX, 77230-1439, USA.
authors.forename: Ester
authors.initials: E
authors.lastname: Borras
authors.affiliation: Department of Pathology, UT MD Anderson Cancer Center, Unit 0085, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Taggart
authors.affiliation: Department of Surgical Oncology, UT MD Anderson Cancer Center, Unit 1484, 1400 Pressler St., Houston, TX, 77030, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Cuddy
authors.affiliation: Clinical Cancer Genetics Program, UT MD Anderson Center, Unit 1354, 1155 Pressler St., Houston, TX, 77030, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bannon
authors.affiliation: Clinical Cancer Genetics Program, UT MD Anderson Center, Unit 1354, 1155 Pressler St., Houston, TX, 77030, USA.|Department of Surgical Oncology, UT MD Anderson Cancer Center, Unit 1484, 1400 Pressler St., Houston, TX, 77030, USA.
authors.forename: Y Nancy
authors.initials: YN
authors.lastname: You
authors.affiliation: Clinical Cancer Genetics Program, UT MD Anderson Center, Unit 1354, 1155 Pressler St., Houston, TX, 77030, USA.|Department of Gastroenterology, Hepatology, and Nutrition, UT MD Anderson Cancer Center, Unit 1466, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lynch
authors.affiliation: Department of Gynecologic Oncology, UT MD Anderson Cancer Center, Unit 1362, P.O. Box 301439, Houston, TX, 77230-1439, USA.
authors.forename: Pedro T
authors.initials: PT
authors.lastname: Ramirez
authors.affiliation: Clinical Cancer Genetics Program, UT MD Anderson Center, Unit 1354, 1155 Pressler St., Houston, TX, 77030, USA.|Department of Gastroenterology, Hepatology, and Nutrition, UT MD Anderson Cancer Center, Unit 1466, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Rodriguez-Bigas
authors.affiliation: Clinical Cancer Genetics Program, UT MD Anderson Center, Unit 1354, 1155 Pressler St., Houston, TX, 77030, USA. evilar@mdanderson.org.|Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Unit 1360, P.O. Box 301439, Houston, TX, 77230-1439, USA. evilar@mdanderson.org.|Department of Gastrointestinal Medical Oncology, UT MD Anderson Center Center, Unit 426, 1515 Holcombe Blvd., Houston, TX, 77030, USA. evilar@mdanderson.org.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010375:Pedigree; D055815:Young Adult
chemical_list: C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2
keywords: Constitutional mismatch repair deficiency; Lynch syndrome; Variant of uncertain significance