Clinical challenges in interpreting multiple pathogenic mutations in single patients

Slaught, Christa; Berry, Elizabeth G.; Bacik, Lindsay; Skalet, Alison H.; Anadiotis, George; Tuohy, Therese; Leachman, Sancy A.

doi:10.1186/s13053-021-00172-3

Hereditary Cancer in Clinical Practice

Table 1 Classic Presentations of Tumor Predisposition Syndromes and the Molecular and Clinical Characterization of Two Individuals with Multiple Pathogenic Mutations

From: Clinical challenges in interpreting multiple pathogenic mutations in single patients

Table 1. Classic Presentations of Tumor Predisposition Syndromes and the Molecular and Clinical Characterization of Two Individuals with Multiple Pathogenic Mutations
	BAP1 Mutation			MSH6 Mutation			RECQL4 Mutation
Gene Information	Gene type: Nuclear-localized deubiquitinase enzyme Syndrome: BAP-1 Tumor predisposition syndrome Inheritance: AD Associated malignancies: Uveal melanoma, mesothelioma, clear cell renal cell carcinoma, atypical Spitz tumors, cutaneous melanoma, basal cell carcinoma Other Malignancies: Meningioma, cholangiocarcinoma, lung cancer, breast cancer, ovarian cancer			Gene type: Mismatch repair gene Syndrome: Lynch Syndrome Inheritance: AD Associated malignancies: Colorectal cancer, endometrial cancer, ovarian cancer, urothelial cancer, CNS cancer, GI cancer, pancreatic cancer Other malignancies: Breast cancer			Gene type: DNA helicase gene Syndromes: Rothmund-Thompson syndrome (RTS), Baller-Gerold syndrome (BGS), RAPADILINO syndrome Inheritance: AR Associated malignancies: Osteosarcoma, Lymphoma, keratinocyte carcinomas (RTS, BGS)
Gene Information	Variant	Pathogenicity	Associated Tumors	Variant	Pathogenicity	Associated Tumors	Variant	Pathogenicity	Associated Tumors	Other Non-syndromic Cancers
Family 1^a
Patient 1^b	Ex12 c.1185dupA (p.Asp396Argfs^f2)	Pathogenic	Basal cell carcinoma of face (×2)	Intron 9 c.4002-2A > G (splice acceptor)	Likely pathogenic	Colon cancer (loss of MSH6)	Exon 14 c.2296C > T (p.Gln757^f)	Pathogenic (hetero-zygous)	Basal cell carcinoma of face (×2)	Hepatocellular carcinoma with recurrence, Lung cancer
Mother	Declined testing		Breast cancer	Declined testing		Breast cancer	Declined testing
Father	Declined testing			Declined testing		Bladder cancer	Declined Testing
Sister	Declined testing		Breast cancer	Declined testing		Breast cancer	Declined testing
Brother	Declined testing			Declined testing			Declined testing			Prostate cancer
Family 2
Patient 2^c (IV-5)	c.38-1G > A	Likely pathogenic		NEGATIVE
Mother	NEGATIVE			Ex3_9del	Pathogenic	Breast cancer
Father	Not tested		Renal cell carcinoma	Not tested
Sister 1 (IV-3)	NEGATIVE			NEGATIVE						Non-melanoma skin cancer
Sister 2^d (IV-4)	NEGATIVE		Breast cancer (intact MLH1, MSH2, MSH6 and PMS2)	Ex3_9del	Pathogenic	Colon cancer (loss of MSH6), Endometrial cancer
Sister 3 (IV-6)	c.38-1G > A	Likely pathogenic		Ex3_9del	Pathogenic	Precancerous colon polyps
Paternal Uncle	Not tested		Cutaneous melanoma	Not tested
Paternal Cousin^e	Not tested		Ocular melanoma, Renal cell carcinoma	Not tested

VUS Variants of unknown significance
^aAll family members for Patient 1 declined genetic testing due to concerns for discrimination by insurance companies
^bPatient 1: The proband and index case for Family 1. Diagnosed with fibrolamellar hepatocellular carcinoma at age 38 and underwent left hepatic lobectomy (initial staging unknown). At age 56, she was found to have locally recurrent hepatocellular carcinoma, requiring wedge resection. On peri-operative imaging, she was also diagnosed with primary lung cancer and underwent left upper lung lobectomy and mediastinal lymph node resection (well- to moderately-differentiated adenocarcinoma with bronchioloalveolar carcinoma features, stage 2A). She had two basal cell carcinomas (BCCs) of the face at ages 58 and 60 treated with Mohs micrographic surgery. At age 67, she was diagnosed with colon cancer requiring right hemicolectomy (poorly differentiated adenocarcinoma with loss of MSH6 on immunohistochemistry, stage 1)
^cPatient 2: Proband for family 2
^dSister 2 (IV-4 on pedigree 2): The index case for Family 2. At age 54, she underwent right hemicolectomy that revealed a primary colon cancer (moderately differentiated mucinous adenocarcinoma, stage 2). Loss of nuclear expression of MSH6 suggested a high probability of Lynch syndrome and Ambry Genetics panel testing revealed an MSH6 EX3-9del. She subsequently underwent a prophylactic TAHBSO, which revealed early endometrial cancer (grade 1, stage IA). At age 55, she was diagnosed with left breast cancer on routine mammography (ER/PR negative, stage 1B). Immunohistochemical studies performed on the breast biopsy tissue demonstrated intact expression of DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2, suggesting that her breast cancer was sporadic and not associated with microsatellite instability
^ePaternal Cousin: Renal cell carcinoma (stage 4)
^fMalignancies are color-coded according to the patients and mutations they have been associated with (BAP1, BAP1 and MSH6, MSH6, RECQL4, BAP1 and RECQL4)

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ISSN: 1897-4287

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