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]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_001126112.2(TP53):c.1102C>T (p.His368Tyr)

CA000039

188342 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: df7ff2a6-8eee-4415-9d93-3b8300c33fbb
Approved on: 2021-04-19
Published on: 2021-06-16

HGVS expressions

NM_001126112.2:c.1102C>T
NM_001126112.2(TP53):c.1102C>T (p.His368Tyr)
ENST00000269305.9:c.1102C>T
ENST00000269305.8:c.1102C>T
ENST00000359597.8:n.994-3445C>T
ENST00000413465.6:n.782+4492C>T
ENST00000420246.6:c.*209C>T
ENST00000445888.6:c.1102C>T
ENST00000455263.6:c.*121C>T
ENST00000504290.5:c.*121C>T
ENST00000504937.5:c.706C>T
ENST00000510385.5:c.*209C>T
ENST00000576024.1:n.55C>T
ENST00000610292.4:c.985C>T
ENST00000610538.4:c.*121C>T
ENST00000610623.4:c.*121C>T
ENST00000615910.4:n.1069C>T
ENST00000617185.4:c.*209C>T
ENST00000618944.4:c.*209C>T
ENST00000619186.4:c.625C>T
ENST00000619485.4:c.985C>T
ENST00000620739.4:c.985C>T
ENST00000622645.4:c.*209C>T
ENST00000635293.1:c.983+920C>T
NM_000546.5:c.1102C>T
NM_001126113.2:c.*121C>T
NM_001126114.2:c.*209C>T
NM_001126115.1:c.706C>T
NM_001126116.1:c.*209C>T
NM_001126117.1:c.*121C>T
NM_001126118.1:c.985C>T
NM_001276695.1:c.*121C>T
NM_001276696.1:c.*209C>T
NM_001276697.1:c.625C>T
NM_001276698.1:c.*209C>T
NM_001276699.1:c.*121C>T
NM_001276760.1:c.985C>T
NM_001276761.1:c.985C>T
NM_001276695.2:c.*121C>T
NM_001276696.2:c.*209C>T
NM_001276697.2:c.625C>T
NM_001276698.2:c.*209C>T
NM_001276699.2:c.*121C>T
NM_001276760.2:c.985C>T
NM_001276761.2:c.985C>T
NM_000546.6:c.1102C>T
NM_001126112.3:c.1102C>T
NM_001126113.3:c.*121C>T
NM_001126114.3:c.*209C>T
NM_001126115.2:c.706C>T
NM_001126116.2:c.*209C>T
NM_001126117.2:c.*121C>T
NM_001126118.2:c.985C>T
NM_001276695.3:c.*121C>T
NM_001276696.3:c.*209C>T
NM_001276697.3:c.625C>T
NM_001276698.3:c.*209C>T
NM_001276699.3:c.*121C>T
NM_001276760.3:c.985C>T
NM_001276761.3:c.985C>T
NC_000017.11:g.7669689G>A
CM000679.2:g.7669689G>A
NC_000017.10:g.7573007G>A
CM000679.1:g.7573007G>A
NC_000017.9:g.7513732G>A
NG_017013.2:g.22862C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
BP4 PM2_Supporting BS3_Supporting
Not Met criteria codes 14
BS2 BS4 BS1 PS2 PS4 PS3 PS1 BP2 BA1 PP1 PP3 PM6 PM1 PM5

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 C0 (BP4). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, TP53 c.1102C>T (p.His368Tyr) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BP4, BS3_Supporting. PM2_Supporting should not be considered conflicting evidence as the variant otherwise meets criteria for Likely Benign classification.
Met criteria codes
BP4
Align GVGD (class C0) and Bayesdel (-0.258202)
PM2_Supporting
Not present in gnomAD.
BS3_Supporting
Kato: Partially functional, Giacomelli: noDNE + noLOF p53WTNutlin3 Z score -0.59 and Etoposide Z score 1.22
Not Met criteria codes
BS2
Color has one case of female unaffected with cancer at age 60+
BS4
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
There is no previous H368Y change
BP2
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Align GVGD (class C0) and Bayesdel (-0.258202). varSEAK: class 1 no splicing effect. splice AI: Acceptor Loss 0.00, Donor Loss 0.00, Acceptor Gain 0.00, Donor Gain 0.03, -18 bp.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not in hot spot defined by TP53 VCEP. Not in cancerhotspots
PM5
Three other variants in ClinVar (VUS), not from TP53 EP, H378N, H368Q
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