Table 4 Clinically impactful germline mutations
PIP ID | Diagnosis | Alteration | Mutation | Change | Mutation type | Clinical utility | Implication | Previously known or suspected |
|---|---|---|---|---|---|---|---|---|
Hematologic conditions | ||||||||
14-19751 | HLH | MLL2 | c.11640_11640delG; c.15631G > A | p.M3881Cfs*9 (de novo); p.E5211K | Compound heterozygous, frameshift | Diagnostic | Kabuki syndrome; Transplantation withheld | No |
15-90485 | HLH | C1QA | c.622C > T | p.Gln208Ter | Homozygous, nonsense | Diagnostic | C1Q deficiency | No |
15-33031 | MDS | GATA2 (de novo) | c.16delG | p.(E6fs) | Heterozygous, frameshift | Supports transplant recommendation; Genetic counseling for family | Increased risk for developing AML and MDS | No |
14-92247 | ALL | PMS2 | c.1376C > G | p.S459X | Homozygous, missense | Diagnostic; Health maintenance/ Genetic counseling | Constitutional mismatch repair deficiency syndrome; Lynch syndrome (parents) | No |
15-46877 | HLH | XIAP | c.1328G > C | p.R443P | Missense | Diagnostic | X-linked lymphoproliferative syndrome 2 (XLP2); Transplantation recommended | No |
14-19750 | AML | RUNX1 | c.806-2A > G | r.Spl? | Heterozygous splice site | Diagnostic | Familial platelet disorder; Transplantation donor changed from sibling to unrelated donor | No |
Solid tumors | ||||||||
14-56374 | Hepatoblastoma | APC | c.3340C > T | p.R1114 | Nonsense | Diagnostic; Health maintenance/ Genetic counseling | Familial adenomatous polyposis | Yes |
15-33544 | Poorly differentiated carcinoma with focal neuroendocrine differentiation | APC (de novo) | c.4660_4661insA | p.E1554fs | Frameshift | Diagnostic; Health maintenance/ Genetic counseling | Gardner syndrome; Familial adenomatous polyposis | No |
15-35162 | Osteosarcoma | RB1 | c.1216-3A > G | p.? | Splice site | Health maintenance/ Genetic counseling | Increased risk for developing other cancers | Yes |
15-44470 | Medulloblastoma | ATM | c.566G > A; c.8266A > T | p.R189K; p.K2756* | Missense, nonsense | Health maintenance/ Genetic counseling | Increased risk for developing other cancers | No |
15-78886a | Pineoblastoma | UGT1A1 | *28 allele (“(TA)7TAA”) | Homozygous | Pharmacogenomic | Drug sensitivity | No | |
15-78886a | Pineoblastoma | DICER1 | c.4807dupC | p.L1603Pfs | Frameshift | Health maintenance/ Genetic counseling | Risk of ovarian Sertoli-Leydig cell tumor | No |
15-17264 | Hepatocellular carcinoma | UGT1A1 | *28 allele | Heterozygous | Pharmacogenomic | Drug sensitivity | No | |
ACMG secondary findings | ||||||||
15-29224 | AML | TP53 | c. 644G > A | p.S215N | Missense | Affects therapy; Health maintenance/ Genetic counseling | Explains lack of response to conventional therapy; Increased risk for developing other cancers | No |
14-59462 | Nested stromal epithelial tumor of the liver | BRCA1 | c.68._69delAG | p.Glu23Valfs | Frameshift | Health maintenance/ Genetic counseling | Breast cancer | No |
16-88073 | Ependymoma | BRCA1 | c.5587_5594delGTAGCACT | p.V1863Lfs*35 | Frameshift | Health maintenance/ Genetic counseling | Breast cancer | No |
14-75899 | Neuroblastoma | RYR1 | c.6838G > A | p.V2280I | Missense | Health maintenance/ Genetic counseling | Malignant hyperthermia | No |
14-13487 | Osteosarcoma | TNNT2 | c.422G > A | p.Arg141Gln | Heterozygous | Health maintenance/ Genetic counseling | Dilated cardiomyopathy | No |
15-34296 | Ependymoma | VHL | c.539 T > C | p.I180T | Missense | Health maintenance/ Genetic counseling | Von Hippel Lindau syndrome | No |