Table 1:
Characteristics of families and probands found to carry TP53 c.1000C>G; p.G334R substitution
| Satisfies LFS Criteria7 | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Fam ID1 | Site2 | Race / AJ3 | Sex | Allele | TP53 Sequencing; BRCA status4 | Clinical Testing / Variant Class5 | Proband cancer history (age at diagnosis)6 | Cancer Family History (age of diagnosis)6 | Classic | Chompret | LFL-Birch | LFL-Eeles | Tumor Studies8 |
| Clinical Cohort | |||||||||||||
| G334R-1 (ref.14) | Penn | EA/AJ | F | G>C | RS/CGT Negative | Ambry / VUS | MP (BC 37yr, BC 65yr, GBM 84yr) | MP (BC 45yr,BC 66yr, Obl); MP (BC 49yr, CRC 49yr, Sarc 52yr (Mut+); MP (BC 59yr,BC 71yr, Mut+); CRC 56yr; MP (Leukemia 74yr, Kidney 74yr, Lymphoma 79yr); BC 60yr; MP (Mel 18yr, Mel 39) | - | X | - | X | NA |
| G334R-2 | Penn | EA/AJ | F | G>C | CGT Negative | Myriad / VUS | BC (Her2+) 30yr | BC 50yr; BC 55yr; Leukemia 55yr | - | X | - | - | Somatic TP53 p.N247I; HRD score=75, MutSigs 1,2,10 |
| G334R-3 | COH / SJ | EA/AJ | F | G>C | CGT Not tested | Ambry / VUS | ACC 18mo | BC 42yr; BC 40yr; Thyroid 32yr | - | X | - | ? | TP53 LOH |
| G334R-4 | CHOP | EA/AJ | F | G>C | TT; CGT BRCA2+ | CHOP/ LP | ACT 17 mo | ACT 4y (Mut+) | - | X | ? | X | TP53 LOH & BRCA2 c.5946delT heterozygous |
| G334R-5 | Cooper | EA/AJ | F | G>C | CGT Negative | GeneDx / VUS | BC 53yr, meningioma | MP (BC 61yr, Lung 84); BC 42yr; BC unk, CRC unk, BC unk, BC 42yr, BC unk | - | - | - | ? | NA |
| G334R-6 | DFCI/ Stanford/ SJ | EA/AJ | F | G>C | CGT Not tested | COH / LP | MP (BC 49yr, Sarc 59yr) | ACC 5yr (Mut+); PA Unk (Mut+); ACC 2yr; Leukemia 2yr; MP (Kidney 75yr, Panc 82yr); BC 57yr; Lung 50yr; Unk site 42yr | - | X | X | X | NA; ACT of TDR - TP53 LOH |
| G334R-7 (ref.10) | CHOP / COH / SK | EA/AJ | F | G>C | CGT Not tested | Sick Kids / LP | ACC 21 mo | Sarc 41yr; Lung 40yr; Lung 58yr | ? | X | ? | ? | NA |
| G334R-8 (ref.20) | DFCI | EA/AJ | F | G>C | RS/CGT Negative | Penn / LP | BC (Her2+) 44yr | BC Unk; Panc 49yr; Brain 12yr; BC 50yr; CRC 60yr; MP (BBC >50yr) | - | ? | ? | ? | NA |
| Genetic Testing Diagnostic Laboratory Cohort (Ambry Genetics Laboratory, Inc.) | |||||||||||||
| G334R-9 | Ambry | EA/AJ | M | G>C | CGT Negative | Ambry / VUS | MP (Kidney 41yr, Panc 69yr) | BC 68yr; BC 60s; BC 50s; Heme 60s | - | - | - | ? | NA |
| G334R-10 | Ambry | Mixed Race/ AJ | F | G>C | CGT Negative | Ambry / VUS | Unaffected 31yr | BC 41yr; Panc 70s | - | - | - | - | NA |
| G334R-11 | Ambry | EA/AJ | F | G>C | CGT Negative | Ambry / VUS | MP (BC 50yr, BC 64yr) | BC 35yr; BC 68yr; MP (BC 41yr, BC 45yr); BC 40s; BC <50yr; Prostate 67yr; BC 60yr | - | - | - | ? | NA |
| G334R-12 | Ambry | EA/AJ | F | G>C | CGT Negative | Ambry / VUS | BC 43yr | Heme <10yr; Lung 62yr; Prostate Unk; BC Unk; BC Unk; BC Unk | - | - | ? | ? | NA |
| G334R-13 | Ambry | EA/AJ | F | G>C | CGT Negative | Ambry / VUS | Unaffected 53yr | BC 53yr; BC Unk; CRC Unk; BC 55yr; Prostate 55yr; BC 60s | - | - | - | ? | NA |
| G334R-14 | Ambry | EA/ Unk | F | G>C | CGT Negative | Ambry / VUS | Skin 62yr | Eso 70yr; Panc 84yr; Lung Unk; Mel 62yr; Heme 62yr; BC Unk; Heme 62yr; BC unk; BC Unk; Brain 62; Gastric 48yr; BC 42yr | - | - | - | ? | NA |
| G334R-15 | Ambry | EA/ Unk | F | G>C | CGT Negative | Ambry / VUS | BC 50yr | Pros 60yr; BC 70yr; MP (BC 50yr, BC 68yr, BC 77yr); CRC 80yr | - | - | - | ? | NA |
| G334R-16 | Ambry | EA/ Unk | F | G>C | CGT Negative | Ambry / VUS | BC 65yr | MP (BC 45yr,BC 47yr); BC 65yr; BC 78yr; CRC 80yr | - | - | - | ? | NA |
| MSKCC IMPACT Cohort | |||||||||||||
| G334R-17 | MSKCC | EA/AJ | M | G>C | CGT Negative | MSKDMP / VUS | Panc, 67yr | NA | ? (All criteria) | Somatic TP53 p.K319X (met) | |||
| G334R-18 | MSKCC | EA/AJ | F | G>C | CGT Negative | MSKDMP / VUS | Panc, 72yr | NA | ? (All criteria) | Somatic TP53 E171H* & H168_T170dup | |||
| G334R-19 | MSKCC | AA/ non-AJ | F | G>C | CGT Negative | MSKDMP / VUS | Pituitary adenoma, 36yr | NA | ? (All criteria) | NA | |||
| IARC/Literature Review | |||||||||||||
| G334R-20 (ref.21) | Mayo | Unk /Unk | F | G>C | RS Negative | NA | BC 38yr | NA | ? (All criteria) | NA | |||
| G334R-21 (ref.19) | TCGA | EA/ Unk | F | G>C | RS Negative | Unk / LP | OC 76yr | NA | ? (All criteria) | TP53 LOH (83% VAF) | |||
| G334R-22 (ref.11) | IARC | Unk/ Unk | Unk | G>A | IARC Unknown | Unk/Unk | ACC 2yr | NA | ? | X | ? | ? | NA |
Families which have been previously reported: Proband of family 1(14); Proband of family 7(10); Proband (IARC ID: RAT13-3-I-1) of family 8/IARC-854(20); Proband of family 20(21); Proband (IARC ID: KAN14-1) of family 21/IARC-946(19), Proband (IARC ID: WAS15-12-1) of family 22/IARC-996(11).
Penn: Penn Medicine; CHOP: Children’s Hospital of Philadelphia; COH: City of Hope; DFCI: Dana Farber Cancer Institute; MSKCC: Memorial Sloan Kettering Cancer Center; MSKDMP: Memorial Sloan Kettering Diagnostic Molecular Pathology; SJ: St.Jude; SK: Sick Kids. Family G334R-9 was also reported in IARC. Probands or family members of families 1, 3, and 7 also had testing at Ambry Genetics but are not included in the Clinical Diagnostic Laboratory Cohort.
EA: European American; AJ: Ashkenazi Jewish; Unk: Unknown; Cau: Caucasian
CGT: Clinical Genetic Testing; RS: Research Sequencing; TT: Tumor testing; IARC: International Agency for Research on Cancer
VUS: variant of uncertain significance; LP: likely pathogenic; P: pathogenic
Individuals reported for lineage suspected to carry the mutation, relationships to proband and other cancer family history found in Supplemental Figure 2 and Supplemental Table 2; yr: years; mo: months; MP: multiple primary cancers; BC: breast cancer; ACC: adrenocortical carcinoma, ACT: adrenocortical tumor; Sarc: sarcoma; GBM: glioblastoma; CRC: colorectal; Eso: esophageal; Heme: hematological malignancy NOS; Mel: melanoma; OC: Ovarian Cancer; Panc: pancreatic; PA: Pituitary Adenoma; Obl: obligate carrier of mutation; Mut+: positive for TP53 c.1000G>C
LFS Criteria(3);”X”: Criteria satisfied; “-“: Deduction can be made that diagnostic criteria not met based upon absent reported family history; “?”: Unknown, cannot assess diagnostic criteria (met/not met) due to lack of established lineage or available family history data
LOH: Loss of heterozygosity; cnLOH: Copy neutral Loss of Heterozygosity; ACT: adrenocortical tumor; VAF: Variant allele frequency
NA: Data Not Available