rs148924904
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS3PS2PP3_ModeratePM1PP4_ModeratePS4_SupportingPM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.488A>G variant in TP53 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 163 (p.Tyr163Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID:19556618). This variant has been reported in 2 additional unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs 21601526, 8164043). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, Internal lab contributor: SCV000581096.5). This variant has an allele frequency of 6.196e-7 (1/1613972 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 54 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences) (PM1, PMID:30311369). Computational predictor scores (BayesDel = 0.54; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 16; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000240/MONDO:0018875/009
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 5.16
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 33
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727242
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GnomAD4 genome 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74278
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2025 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the TP53 protein (p.Tyr163Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 8164043, 11051239, 18685109, 19556618, 25584008, 25757876). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127814). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 05, 2024 | The NM_000546.6: c.488A>G variant in TP53 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 163 (p.Tyr163Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). This variant has been reported in 2 additional unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs 21601526, 8164043). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000581096.5). This variant has an allele frequency of 6.196e-7 (1/1613972 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 54 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences) (PM1, PMID: 30311369). Computational predictor scores (BayesDel = 0.54; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 16; VCEP specifications version 2.0; 7/24/2024) - |
Li-Fraumeni syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 14, 2024 | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15037740, 23246812, 25584008]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19556618, 25584008]. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2022 | Published functional studies demonstrate a damaging effect: loss of transcriptional activation and growth suppression activities (Kato et al., 2003; Scian et al., 2004; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 10519380, 16861262, 14559903, 26585234, 22109999, 16173033, 23929122, 20077503, 8164043, 10671690, 17559811, 17606709, 18685109, 21519010, 24651012, 17764544, 25385265, 25149524, 23967324, 17947339, 15077194, 10753186, 12792784, 15308588, 10871862, 15037740, 10567903, 29167553, 29979965, 30720243, 30630526, 30840781, 33300245, 32817165, 15510160, 21343334, 21601526, 25584008) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2021 | The p.Y163C variant (also known as c.488A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 488. The tyrosine at codon 163 is replaced by cysteine, an amino acid with highly dissimilar properties. The p.Y163C variant has been observed as a germline alteration a patient with early-onset osteosarcoma and a family history of central nervous system malignancies (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-30). In addition, this alteration was observed in an individual from a LFS family who was diagnosed with adrenocortical carcinoma at the age of 2.5 years and an anaplastic astrocytoma at the age of 14 (Villani et. al. Lancet Oncology. 2011;12:559). This alteration has also been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer (Yi D et al. Hum. Genomics. 2019 01;13:4) This alteration is located in the functionally critical DNA binding domain of the p53 protein. In multiple yeast-based functional studies, this alteration has been shown to be devoid of transactivation capability and demonstrate dominant negative properties (Chappuis PO et al. Int. J. Cancer 1999 Dec;84(6):587-93; Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis 2007 Feb;28(2):289-98; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Ovarian neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Polyphen
D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.
Vest4
MutPred
Loss of phosphorylation at Y163 (P = 0.0248);Loss of phosphorylation at Y163 (P = 0.0248);.;.;.;.;.;.;.;Loss of phosphorylation at Y163 (P = 0.0248);.;Loss of phosphorylation at Y163 (P = 0.0248);Loss of phosphorylation at Y163 (P = 0.0248);Loss of phosphorylation at Y163 (P = 0.0248);.;.;Loss of phosphorylation at Y163 (P = 0.0248);.;.;.;.;Loss of phosphorylation at Y163 (P = 0.0248);
MVP
MPC
1.9
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at