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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  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.1003C>T (p.Arg335Cys)

CA000009

141159 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2c051651-783e-433a-913d-2201e71b6cb7
Approved on: 2020-09-04
Published on: 2020-09-04

HGVS expressions

NM_000546.5:c.1003C>T
NM_000546.5(TP53):c.1003C>T (p.Arg335Cys)
NM_001126112.2:c.1003C>T
NM_001126113.2:c.*22C>T
NM_001126114.2:c.*110C>T
NM_001126115.1:c.607C>T
NM_001126116.1:c.*110C>T
NM_001126117.1:c.*22C>T
NM_001126118.1:c.886C>T
NM_001276695.1:c.*22C>T
NM_001276696.1:c.*110C>T
NM_001276697.1:c.526C>T
NM_001276698.1:c.*110C>T
NM_001276699.1:c.*22C>T
NM_001276760.1:c.886C>T
NM_001276761.1:c.886C>T
NM_001276695.2:c.*22C>T
NM_001276696.2:c.*110C>T
NM_001276697.2:c.526C>T
NM_001276698.2:c.*110C>T
NM_001276699.2:c.*22C>T
NM_001276760.2:c.886C>T
NM_001276761.2:c.886C>T
ENST00000269305.8:c.1003C>T
ENST00000359597.8:n.993+2829C>T
ENST00000413465.6:n.782+3475C>T
ENST00000420246.6:c.*110C>T
ENST00000445888.6:c.1003C>T
ENST00000455263.6:c.*22C>T
ENST00000504290.5:c.*22C>T
ENST00000504937.5:c.607C>T
ENST00000510385.5:c.*110C>T
ENST00000576024.1:n.54-1016C>T
ENST00000610292.4:c.886C>T
ENST00000610538.4:c.*22C>T
ENST00000610623.4:c.*22C>T
ENST00000615910.4:n.970C>T
ENST00000617185.4:c.*110C>T
ENST00000618944.4:c.*110C>T
ENST00000619186.4:c.526C>T
ENST00000619485.4:c.886C>T
ENST00000620739.4:c.886C>T
ENST00000622645.4:c.*110C>T
ENST00000635293.1:c.886C>T
NC_000017.11:g.7670706G>A
CM000679.2:g.7670706G>A
NC_000017.10:g.7574024G>A
CM000679.1:g.7574024G>A
NC_000017.9:g.7514749G>A
NG_017013.2:g.21845C>T

Uncertain Significance

Met criteria codes 4
BS3 BS2_Supporting PP3 PM2_Supporting
Not Met criteria codes 9
BS1 BP4 BP2 PS1 PS3 PS4 BA1 PM5 PM1

Evidence Links 2

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). Transactivation assays show retained 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). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor (SCV000629764.4). In summary, the clinical significance of TP53 c.1003C>T(p.Arg335Cys) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS3, PP3, BS2_Supporting.
Met criteria codes
BS3
transactivation assays show retained 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.
there is no evidence of a dominant negative effect or loss of function PubMed:12826609
transactivation assays show retained function PubMed:30224644
BS2_Supporting
Absent from FLOSSIES database. Lab has 3 cases of women unaffected with cancer at age 60 (SCV000629764.4).
PP3
Align-GVGD class C25, BayesDel score 0.2751
PM2_Supporting
Absent from gnomAD v2.1.1 (not a filtered variant, the region is covered)
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
In 5/38 occurrences from clinical lab internal data, a pathogenic variant in another gene was reported. None of these occurrences were LFS-like based on the info provided.
PS1
No other variants with same amino acid change in ClinVar
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No cases in the literature.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
There is one other missense variant at this codon in ClinVar, c.1004G>A (p.Arg335His), although it is currently a VUS.
PM1
Not in a hot spot codon, absent from cancerhotspots.org
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