Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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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
Link to MONDO
UUID: 0a1d958f-f7f2-4507-b3b9-11e245172c89
Approved on: 2022-06-27
Published on: 2022-06-27

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)
More

Likely Pathogenic

Met criteria codes 5
PP3_Moderate PM1 PS4_Supporting PM2_Supporting PS3_Moderate
Not Met criteria codes 7
PM5 BS3 BS1 BS2 BP4 PS1 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
PP3_Moderate
aGVGD = C65; BayesDel = 0.2956
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.
PM2_Supporting
Absent from gnomAD (non-cancer) - still absent from v2.1.1 and v.3.1.2 as of 6/3/22
PS3_Moderate
Kato partially functional; Giacomelli DNE + LOF; Kotler LOF
Not Met criteria codes
PM5
P190R (ClinVar: 234061, 1x VUS); P190S (ClinVar: 646725, 2x VUS); P190T (ClinVar: 233197, 1x VUS); None evaluated by VCEP
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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