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.607G>A (p.Val203Met)

CA000292

182933 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9b41bbda-7cef-4743-ad3c-44269b286714
Approved on: 2021-06-02
Published on: 2021-06-16

HGVS expressions

NM_001126112.2:c.607G>A
NM_001126112.2(TP53):c.607G>A (p.Val203Met)
NC_000017.11:g.7674924C>T
CM000679.2:g.7674924C>T
NC_000017.10:g.7578242C>T
CM000679.1:g.7578242C>T
NC_000017.9:g.7518967C>T
NG_017013.2:g.17627G>A
ENST00000269305.9:c.607G>A
ENST00000269305.8:c.607G>A
ENST00000359597.8:n.607G>A
ENST00000413465.6:n.607G>A
ENST00000420246.6:c.607G>A
ENST00000445888.6:c.607G>A
ENST00000455263.6:c.607G>A
ENST00000504290.5:c.211G>A
ENST00000504937.5:c.211G>A
ENST00000505014.5:n.863G>A
ENST00000509690.5:c.211G>A
ENST00000510385.5:c.211G>A
ENST00000514944.5:c.328G>A
ENST00000574684.1:n.67+129G>A
ENST00000610292.4:c.490G>A
ENST00000610538.4:c.490G>A
ENST00000610623.4:c.130G>A
ENST00000615910.4:n.574G>A
ENST00000617185.4:c.607G>A
ENST00000618944.4:c.130G>A
ENST00000619186.4:c.130G>A
ENST00000619485.4:c.490G>A
ENST00000620739.4:c.490G>A
ENST00000622645.4:c.490G>A
ENST00000635293.1:c.490G>A
NM_000546.5:c.607G>A
NM_001126113.2:c.607G>A
NM_001126114.2:c.607G>A
NM_001126115.1:c.211G>A
NM_001126116.1:c.211G>A
NM_001126117.1:c.211G>A
NM_001126118.1:c.490G>A
NM_001276695.1:c.490G>A
NM_001276696.1:c.490G>A
NM_001276697.1:c.130G>A
NM_001276698.1:c.130G>A
NM_001276699.1:c.130G>A
NM_001276760.1:c.490G>A
NM_001276761.1:c.490G>A
NM_001276695.2:c.490G>A
NM_001276696.2:c.490G>A
NM_001276697.2:c.130G>A
NM_001276698.2:c.130G>A
NM_001276699.2:c.130G>A
NM_001276760.2:c.490G>A
NM_001276761.2:c.490G>A
NM_000546.6:c.607G>A
NM_001126112.3:c.607G>A
NM_001126113.3:c.607G>A
NM_001126114.3:c.607G>A
NM_001126115.2:c.211G>A
NM_001126116.2:c.211G>A
NM_001126117.2:c.211G>A
NM_001126118.2:c.490G>A
NM_001276695.3:c.490G>A
NM_001276696.3:c.490G>A
NM_001276697.3:c.130G>A
NM_001276698.3:c.130G>A
NM_001276699.3:c.130G>A
NM_001276760.3:c.490G>A
NM_001276761.3:c.490G>A

Uncertain Significance

Met criteria codes 3
PM2_Supporting PS4_Supporting BP4
Not Met criteria codes 14
PS2 PS3 PS1 PP1 PP3 PM1 PM5 PM6 BA1 BS2 BS4 BS3 BS1 BP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is absent from the gnomAD non-cancer v2.1.1 dataset (PM2_supporting). Transactivation assays show partial function according to Kato, et al (PMID: 12826609) with evidence of a dominant negative effect, but not loss of function according to Giacomelli, et al. (PMID: 30224644) and Kotler et al. (PMID: 29979965) (BS3_supporting). The VCEP considers the variant scores borderline/conflicting and therefore overrode application of the BS3_Supporting code. This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been identified in one pediatric patient with adrenocortical tumor (PMID: 33178583) and in one patient meeting Chompret criteria (internal laboratory contributor) (PS4_supporting). In summary, TP53 c.607G>A; p.Val203Met meets criteria to be classified as uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting; BP4, PS4_supporting.
Met criteria codes
PM2_Supporting
Not found in gnomAD dataset v2.1.1
PS4_Supporting
Invitae, GeneDx and Ambry report one case each of a patient meeting Chompret. However, GeneDx notes that patient also had testing through Ambry. Invitae indicated that the patient had previous testing in GeneDx and Ambry. Therefore, It is assumed that the reports refer to the same person. Total points = 0.5 An additional case meeting Chompret criteria in the literature (Meile 2020) gives 0.5 proband points. A total of 1 point
BP4
Align-GVGD class = C0 + BayesDel = 0.0264455
Not Met criteria codes
PS2
No data available
PS3
Kato (partially functional), no LOF by Kotler (-1.067), DNE_notLOF (Giacomelli, unclassified). Conflicting evidence. Code not applied.
PS1
There is no previously established pathogenic variant p.V203M with a different nucleotide change. varSEAK predicts no splicing effect (Class 1)
PP1
No data available
PP3
Align-GVGD class = C0 + BayesDel = 0.0264455
PM1
Codon 203 is not considered a hotspot. Cancerhotspots.org does not include somatic observations for V203, regardless of aminoacid change.
PM5
There is no variant in residue V203 determined to be pathogenic by the ClinGen TP53 Expert Panel.
PM6
No data available
BA1
Not found in gnomAD dataset v2.1.1
BS2
None
BS4
No data available
BS3
Kato (partially functional), no LOF by Kotler (-1.067), DNE_notLOF (Giacomelli, unclassified). BS3_supporting code overridden, Conflicting/borderline evidence. Code not applied.
BS1
Not found in gnomAD dataset v2.1.1
BP2
Lab B: Yes, PMS2 PATH in F (possibly mosaic TP53) with ovarian cancer in 70s
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.