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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000546.6(TP53):c.997C>T (p.Arg333Cys)

CA000530

184745 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4bdb59d3-0848-40a4-91d8-1adc8f8effef
Approved on: 2021-04-19
Published on: 2021-06-16

HGVS expressions

NM_000546.6:c.997C>T
NM_000546.6(TP53):c.997C>T (p.Arg333Cys)
ENST00000269305.9:c.997C>T
ENST00000269305.8:c.997C>T
ENST00000359597.8:n.993+2823C>T
ENST00000413465.6:n.782+3469C>T
ENST00000420246.6:c.*104C>T
ENST00000445888.6:c.997C>T
ENST00000455263.6:c.*16C>T
ENST00000504290.5:c.*16C>T
ENST00000504937.5:c.601C>T
ENST00000510385.5:c.*104C>T
ENST00000576024.1:n.54-1022C>T
ENST00000610292.4:c.880C>T
ENST00000610538.4:c.*16C>T
ENST00000610623.4:c.*16C>T
ENST00000615910.4:n.964C>T
ENST00000617185.4:c.*104C>T
ENST00000618944.4:c.*104C>T
ENST00000619186.4:c.520C>T
ENST00000619485.4:c.880C>T
ENST00000620739.4:c.880C>T
ENST00000622645.4:c.*104C>T
ENST00000635293.1:c.880C>T
NM_000546.5:c.997C>T
NM_001126112.2:c.997C>T
NM_001126113.2:c.*16C>T
NM_001126114.2:c.*104C>T
NM_001126115.1:c.601C>T
NM_001126116.1:c.*104C>T
NM_001126117.1:c.*16C>T
NM_001126118.1:c.880C>T
NM_001276695.1:c.*16C>T
NM_001276696.1:c.*104C>T
NM_001276697.1:c.520C>T
NM_001276698.1:c.*104C>T
NM_001276699.1:c.*16C>T
NM_001276760.1:c.880C>T
NM_001276761.1:c.880C>T
NM_001276695.2:c.*16C>T
NM_001276696.2:c.*104C>T
NM_001276697.2:c.520C>T
NM_001276698.2:c.*104C>T
NM_001276699.2:c.*16C>T
NM_001276760.2:c.880C>T
NM_001276761.2:c.880C>T
NM_001126112.3:c.997C>T
NM_001126113.3:c.*16C>T
NM_001126114.3:c.*104C>T
NM_001126115.2:c.601C>T
NM_001126116.2:c.*104C>T
NM_001126117.2:c.*16C>T
NM_001126118.2:c.880C>T
NM_001276695.3:c.*16C>T
NM_001276696.3:c.*104C>T
NM_001276697.3:c.520C>T
NM_001276698.3:c.*104C>T
NM_001276699.3:c.*16C>T
NM_001276760.3:c.880C>T
NM_001276761.3:c.880C>T
NC_000017.11:g.7670712G>A
CM000679.2:g.7670712G>A
NC_000017.10:g.7574030G>A
CM000679.1:g.7574030G>A
NC_000017.9:g.7514755G>A
NG_017013.2:g.21839C>T
More

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
PP3 BS2_Supporting BS3
Not Met criteria codes 13
BA1 PS2 PS4 PS3 PS1 PP1 PM6 PM2 PM1 PM5 BS4 BS1 BP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] function 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; PMID: 12826609, 30224644). In this case, a single supporting evidence code (PP3) should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. In summary, TP53 c.997C>T (p.Arg333Cys) 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: PP3, BS2_Supporting, BS3.
Met criteria codes
PP3
This variant has a BayesDel score > 0.16 (0.2370) and Align GVGD (Zebrafish) is Class 35 (PP3).
BS2_Supporting
Identified in GeneDx is 2 females cancer free at age 60+. Identified in 3 females cancer free at 60+ at Invitae. Identified in 2 females cancer free at 60+ years at Ambry.
BS3
Transactivation assays show retainedfunction according to Kato, et al. (102.3% mean transactivation activity (>75%)) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (p53WTNutlin3 Z-score -1.179 (< 0.61) and Etoposide Z-score 0.578(> -0.21 )) (BS3; PMID: 12826609, 30224644)
Not Met criteria codes
BA1
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
Seen once in a case meeting Chompret criteria (PMID: 2389440) for 0.5 proband points (Proband with acute leukemia NOS and Ewings sarcoma at 10 and 16 years of age, respectively). Seen in a proband who met revised Chompret at Invitae. However, the TP53 VCEP notes that this variant was seen at least 44 times across two commercial laboratories in individuals that did not appear to have LFS. The VCEP does not feel that the few cases meeting Revised Chompret should be given undue weight in light of this other internal lab data and in conjunction with unaffected female 60+ cases observed leading to BS2 application.
PS3
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
6 total alleles in gnomAD with an overall frequency of 0.002%
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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