rs786203064
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4PM2_SupportingPS4_Supporting
This summary comes from the ClinGen Evidence Repository: 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 or Class C15 (BP4). This variant has been reported in 1 proband meeting Classic LFS criteria (PS4_Supporting; NIH). In summary, the clinical significance of TP53 c.436T>G (p.Trp146Gly) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000190/MONDO:0007903/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.436T>G | p.Trp146Gly | missense_variant | 5/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.436T>G | p.Trp146Gly | missense_variant | 5/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Sep 04, 2020 | 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 or Class C15 (BP4). This variant has been reported in 1 proband meeting Classic LFS criteria (PS4_Supporting; NIH). In summary, the clinical significance of TP53 c.436T>G (p.Trp146Gly) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, BP4. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The p.W146G variant (also known as c.436T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 436. The tryptophan at codon 146 is replaced by glycine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at