Variant: NM_001276761.2:c.365_370del

CA915940817

973858 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 04670dbf-dcc3-4cec-8727-691d183eec54

HGVS expressions

NM_001276761.2:c.365_370del
NC_000017.11:g.7675125_7675130del
CM000679.2:g.7675125_7675130del
NC_000017.10:g.7578443_7578448del
CM000679.1:g.7578443_7578448del
NC_000017.9:g.7519168_7519173del
NG_017013.2:g.17421_17426del
ENST00000269305.9:c.482_487del
ENST00000269305.8:c.482_487del
ENST00000359597.8:n.482_487del
ENST00000413465.6:n.482_487del
ENST00000420246.6:c.482_487del
ENST00000445888.6:c.482_487del
ENST00000455263.6:c.482_487del
ENST00000504290.5:c.86_91del
ENST00000504937.5:c.86_91del
ENST00000505014.5:n.738_743del
ENST00000508793.5:c.482_487del
ENST00000509690.5:c.86_91del
ENST00000510385.5:c.86_91del
ENST00000514944.5:c.203_208del
ENST00000610292.4:c.365_370del
ENST00000610538.4:c.365_370del
ENST00000610623.4:c.5_10del
ENST00000615910.4:n.449_454del
ENST00000617185.4:c.482_487del
ENST00000618944.4:c.5_10del
ENST00000619186.4:c.5_10del
ENST00000619485.4:c.365_370del
ENST00000620739.4:c.365_370del
ENST00000622645.4:c.365_370del
ENST00000635293.1:c.365_370del
NM_000546.5:c.482_487del
NM_001126112.2:c.482_487del
NM_001126113.2:c.482_487del
NM_001126114.2:c.482_487del
NM_001126115.1:c.86_91del
NM_001126116.1:c.86_91del
NM_001126117.1:c.86_91del
NM_001126118.1:c.365_370del
NM_001276695.1:c.365_370del
NM_001276696.1:c.365_370del
NM_001276697.1:c.5_10del
NM_001276698.1:c.5_10del
NM_001276699.1:c.5_10del
NM_001276760.1:c.365_370del
NM_001276761.1:c.365_370del
NM_001276695.2:c.365_370del
NM_001276696.2:c.365_370del
NM_001276697.2:c.5_10del
NM_001276698.2:c.5_10del
NM_001276699.2:c.5_10del
NM_001276760.2:c.365_370del
NM_000546.6:c.482_487del
NM_001126112.3:c.482_487del
NM_001126113.3:c.482_487del
NM_001126114.3:c.482_487del
NM_001126115.2:c.86_91del
NM_001126116.2:c.86_91del
NM_001126117.2:c.86_91del
NM_001126118.2:c.365_370del
NM_001276695.3:c.365_370del
NM_001276696.3:c.365_370del
NM_001276697.3:c.5_10del
NM_001276698.3:c.5_10del
NM_001276699.3:c.5_10del
NM_001276760.3:c.365_370del
NM_001276761.3:c.365_370del
NM_000546.6(TP53):c.482_487del (p.Ala161_Tyr163delinsAsp)

Uncertain Significance

• Met criteria codes: PP1 PM2_Supporting PM5 PS4_Supporting

• Not Met criteria codes: PS3 PS2 PM6 PM1 BA1 BS2 BS3 BS4 BS1 BP2

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

This variant has been reported in 1 family meeting Classic LFS criteria (PS4_Supporting; internal clinical contributors). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are 2 TP53 pathogenic/likely pathogenic variants (p.Y163C, p.A161D) previously reported at this codon (PM5; ClinVar ID 127814, 422295). While rule codes specify application of PM5 code only for those variants found to be Pathogenic, expert opinion in this case allowed for application of PM5 at moderate weight despite one residue's classification as likely pathogenic. This variant was found to co-segregate with disease in multiple affected family members, with 4 meioses observed (PP1_Moderate; internal laboratory contributors). In summary, the clinical significance of TP53 c.482_487del (p.Ala161_Tyr163delinsAsp) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PM2_Supporting, PM5, PP1.

Met criteria codes

• PP1: 4 meioses reported in the family shared by NCI/Johns Hopkins/Dana Farber
• PM2_Supporting: Variant absent from database
• PM5: Disrupts the p.Tyr163 amino acid residue in TP53. This variant is classified as P by VCEP. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 8164043, 18685109, 19556618, 12826609, 16861262). Suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. A161 is curated as LP using VCEP ruleset.
• PS4_Supporting: Proband in internal clinical case meets Classical criteria = 1 point. No other cases found in the literature

Not Met criteria codes

• PS3: Can't use
• PS2: No de novo cases found
• PM6: No de novo cases found
• PM1: Can't use
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: Not found in FLOSSIES
• BS3: Can't use
• BS4: No cases in the literature and proband's family not tested
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No cases in literature

Approved on: 2022-03-14

Published on: 2022-03-18