. Author manuscript; available in PMC: 2018 Sep 5.

Published in final edited form as: JAMA. 2017 Sep 5;318(9):825–835. doi: 10.1001/jama.2017.11137

Table 3.

Cases With Germline Actionable Incremental Nonfounder Variants Not Predicted by Phenotype-Based Guidelines, Arranged According to Penetrance and Including Tumor Status of the Gene With Inherited Mutation^a

Case No.	Tumor Type^b	Gene With Inherited Mutation	Tumor Status of Gene With Inherited Mutation^c
High Penetrance (n = 26 Cases)
R56	Biliary	PALB2	WT
R155^d	Biliary	BRCA2	WT
R80	Bladder	MSH6	Second mutation (h+, m−)
R102	Bladder	MSH2	WT (h+, m+)
R116	Bladder	MSH6	LOH (h+, m−)
R116	Bladder	APC	WT
R197	Breast	SDHA	LOH
R26^d	Pancreatic	BRCA2	LOH
R101	Pancreatic	CDKN2A	WT
R106	Pancreatic	BRCA2	WT
R190	Pancreatic	BRCA2	ND
R50	Prostate	BRCA1^e	ND
R53	Prostate	BRCA2	LOH
R79^d	Prostate	BRCA2^e	LOH
R111	Prostate	MSH2^e	LOH (h+, m+)
R111	Prostate	FH^e	WT
R132	Prostate	PALB2^e	ND
R135^f	Prostate	MSH6^e	WT (h−, m−)
R151^d	Prostate	BRCA2^e	Second mutation
R166^d	Prostate	PMS2^e	LOH (h+, m+)
R182	Prostate	BRCA2^e	WT
R192	Prostate	BRCA2^e	WT
R205	Prostate	BRCA2^e	Second mutation
R6	Renal cell	PALB2	WT
R117	Renal cell	VHL	LOH
R180	Renal cell	SDHA	CN-LOH
R134^d	Mesothelioma	BAP1	LOH
R164^d	Ampullary	BRCA2	LOH
Moderate Penetrance (n = 24 Cases)
R136	Colorectal	ATM	WT
R136	Colorectal	APC^g	WT
R69	Colorectal	BRIP1	WT
R201	Esophagogastric	ATM	ND
R38	Pancreatic	ATM	LOH
R173	Pancreatic	CHEK2	WT
R188	Pancreatic	ATM	Second mutation
R87	Prostate	MITF	WT
R118	Prostate	MITF	WT
R4	Prostate	CHEK2^e	WT
R17^d	Prostate	NBN^e	WT
R18	Prostate	CHEK2^e	WT
R31	Prostate	BRIP1^e	LOH
R55	Prostate	BRIP1^e	LOH
R62	Prostate	ATM^e	WT
R66	Prostate	NBN^e	LOH
R71	Prostate	ATM^e	Second mutation
R108^d	Prostate	ATM^e	ND
R120	Prostate	ATM^e	ND
R150^d	Prostate	ATM^e	ND
R195	Prostate	ATM^e	LOH
R147^d	Renal cell	CHEK2	ND
R189	Renal cell	CHEK2	WT
R129^d	Non–small cell lung	RAD51D	ND
R185^d	Endometrial	CHEK2	ND
Low Penetrance (n = 8 Cases)
R20^d	Colorectal	MUTYH	ND
R91	Pancreatic	MUTYH	WT
R59	Prostate	MUTYH	LOH
R127	Prostate	MUTYH	ND
R133	Prostate	MUTYH	WT
R128	Renal cell	MUTYH	LOH
R82	Unknown primary	MUTYH	WT
R149	Adrenocortical	MUTYH	LOH

Abbreviations: CN, copy neutral; LOH, loss of heterozygosity; ND, not determined; WT, wild type.

The breakdown of cases by penetrance type (26 high-penetrance, 24 moderate-penetrance, and 8 low-penetrance cases) corresponds to those listed at the bottom of the Figure in parentheses with the exception of the single case noted in footnote f.

Represents the sample for which tumor profiling had been performed.

The following indicate the tumor status: LOH, status of the second allele in the tumor of the gene mutated in the germline; WT, that the second allele was not mutated; second mutation, the second allele was mutated in the tumor in the same gene demonstrating a germline variant; CN-LOH, LOH in the tumor not accompanied by changes of copy number in the chromosomal region around the mutation; ND, cases in which zygosity was not determined; h+, hypermutated tumor profile (≥20 mutations); h−, not hypermutated tumor profile (<20 mutations); m+, microsatellite instability high (MSI sensor positive; ≥10% of loci on the sequencing panel); and m−, microsatellite instability negative (MSI sensor negative; <10% of loci on the sequencing panel).

Patients had additional cancer diagnoses.

Cases with DNA repair genes associated with advanced prostate cancer in the article by Pritchard et al.¹⁶

The MSH6 variant in this case is a founder variant (see eTable in Supplement 3) and was not counted toward the total of high-penetrance cases with nonfounder variants, but it is included here to illustrate one of the incremental cases with hypermutation status and MSI sensor data.

Refers to a second nonincremental variant.