Variant: NM_001126112.2(TP53):c.569C>T (p.Pro190Leu)

CA16620625

418517 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 0a1d958f-f7f2-4507-b3b9-11e245172c89

HGVS expressions

NM_001126112.2:c.569C>T
NM_001126112.2(TP53):c.569C>T (p.Pro190Leu)
NC_000017.11:g.7674962G>A
CM000679.2:g.7674962G>A
NC_000017.10:g.7578280G>A
CM000679.1:g.7578280G>A
NC_000017.9:g.7519005G>A
NG_017013.2:g.17589C>T
ENST00000269305.9:c.569C>T
ENST00000269305.8:c.569C>T
ENST00000359597.8:n.569C>T
ENST00000413465.6:n.569C>T
ENST00000420246.6:c.569C>T
ENST00000445888.6:c.569C>T
ENST00000455263.6:c.569C>T
ENST00000504290.5:c.173C>T
ENST00000504937.5:c.173C>T
ENST00000505014.5:n.825C>T
ENST00000509690.5:c.173C>T
ENST00000510385.5:c.173C>T
ENST00000514944.5:c.290C>T
ENST00000574684.1:n.67+91C>T
ENST00000610292.4:c.452C>T
ENST00000610538.4:c.452C>T
ENST00000610623.4:c.92C>T
ENST00000615910.4:n.536C>T
ENST00000617185.4:c.569C>T
ENST00000618944.4:c.92C>T
ENST00000619186.4:c.92C>T
ENST00000619485.4:c.452C>T
ENST00000620739.4:c.452C>T
ENST00000622645.4:c.452C>T
ENST00000635293.1:c.452C>T
NM_000546.5:c.569C>T
NM_001126113.2:c.569C>T
NM_001126114.2:c.569C>T
NM_001126115.1:c.173C>T
NM_001126116.1:c.173C>T
NM_001126117.1:c.173C>T
NM_001126118.1:c.452C>T
NM_001276695.1:c.452C>T
NM_001276696.1:c.452C>T
NM_001276697.1:c.92C>T
NM_001276698.1:c.92C>T
NM_001276699.1:c.92C>T
NM_001276760.1:c.452C>T
NM_001276761.1:c.452C>T
NM_001276695.2:c.452C>T
NM_001276696.2:c.452C>T
NM_001276697.2:c.92C>T
NM_001276698.2:c.92C>T
NM_001276699.2:c.92C>T
NM_001276760.2:c.452C>T
NM_001276761.2:c.452C>T
NM_000546.6:c.569C>T
NM_001126112.3:c.569C>T
NM_001126113.3:c.569C>T
NM_001126114.3:c.569C>T
NM_001126115.2:c.173C>T
NM_001126116.2:c.173C>T
NM_001126117.2:c.173C>T
NM_001126118.2:c.452C>T
NM_001276695.3:c.452C>T
NM_001276696.3:c.452C>T
NM_001276697.3:c.92C>T
NM_001276698.3:c.92C>T
NM_001276699.3:c.92C>T
NM_001276760.3:c.452C>T
NM_001276761.3:c.452C>T
NM_000546.6(TP53):c.569C>T (p.Pro190Leu)

Likely Pathogenic

• Met criteria codes: PM1 PS4_Supporting PS3_Moderate PP3_Moderate PM2_Supporting

• Not Met criteria codes: PS1 PM5 BA1 BS3 BS1 BS2 BP4

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a partially functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3_Moderate; PMID: 12826609, 30224644). This variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; Invitae, GeneDx/NIH). In summary, TP53 c.569C>T (p.Pro190Leu) meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3_Moderate, PS4_Supporting.

Met criteria codes

• PM1: Yes, 12/17 samples on cancerhotspots.com
• PS4_Supporting: 1 proband (NIH/GeneDx) meeting Chompret (0.5 pts). 1 proband (Invitae) meeting Chompret. Not seen by Color.
• PS3_Moderate: Kato partially functional; Giacomelli DNE + LOF; Kotler LOF
• PP3_Moderate: aGVGD = C65; BayesDel = 0.2956
• PM2_Supporting: Absent from gnomAD (non-cancer) - still absent from v2.1.1 and v.3.1.2 as of 6/3/22

Not Met criteria codes

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: P190R (ClinVar: 234061, 1x VUS); P190S (ClinVar: 646725, 2x VUS); P190T (ClinVar: 233197, 1x VUS); None evaluated by VCEP
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: Not present in FLOSSIES. Internal data provided by one ClinVar submitter but not other.
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-06-27

Published on: 2022-06-27