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rs28934576

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.818G>T(p.Arg273Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R273H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

12
4
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:33

Conservation

PhyloP100: 7.91
Variant links:
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 18 ACMG points.

PM1
In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7673802-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12366.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 17-7673802-C-A is Pathogenic according to our data. Variant chr17-7673802-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 376655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.818G>T p.Arg273Leu missense_variant 8/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.818G>T p.Arg273Leu missense_variant 8/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152054
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251054
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135726
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461808
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152054
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:33
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 12, 2023The p.R273L pathogenic mutation (also known as c.818G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 818. The arginine at codon 273 is replaced by leucine, an amino acid with dissimilar properties. This mutation occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain. Several other mutations have been described at this position and are associated with a classic LFS-associated tumor spectrum (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). This specific alteration has been reported in a family meeting Chompret criteria for Li-Fraumeni Syndrome, and has been identified as a de novo mutation in a patient diagnosed with adrenaocortical carcinoma and rhabdomyosarcoma at 1 year of age (Bougeard Get al. J. Clin. Oncol. 2015 Jul; 33(21):2345-52; Chompret A et al. Br. J. Cancer 2000 Jun; 82(12):1932-7). Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti, P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth Let al. Carcinogenesis 2007 Feb; 28(2):289-98). 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). Based on crystal structure analysis, this position has been shown to be involved in DNA contact and binding (Martin A et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R273L is classified as a pathogenic mutation. -
Li-Fraumeni syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 10, 2023This variant disrupts the p.273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 273 of the TP53 protein (p.Arg273Leu). This variant is present in population databases (rs28934576, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni-associated cancers (PMID: 10864200, 26014290). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376655). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 12826609, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 11, 2017The p.Arg273Leu variant in TP53 has been reported in 6 individuals with TP53-associated cancers, including 1 that was de novo (paternity- confirmed; Chompret 2000, Kyritsis 1994, Monti 2007, Dong 2011 and Bougeard 2015). This variant has also been reported in ClinVar (Variation ID 376655) and has been identified in 1/111470 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28934576), though the allele ratio suggests it may be somatic. Arginine at position 273 is a mutational hotspot in many different types of cancers, and different changes at the same codon (p.Arg273Cys and p.Arg273His) have been reported in multiple families with Li-Fraumeni syndrome. Computational prediction tools suggest that the p.Arg273Leu variant may impact the protein. In vitro functional studies provide some evidence that the p.Arg273Leu variant may impact protein function (Kawamura 1996, Monti 2011, Ory 1994). In summary, the p.Arg273Leu variant is pathogenic Li-Fraumeni syndrome in an autosomal dominant inheritance. -
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Adrenal cortex carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Carcinoma of esophagus Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Squamous cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 23, 2022Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of apoptotic activity, and exhibits a dominant-negative effect (Monti et al., 2007; Monti et al., 2011; Giacomelli et al., 2018; 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: 10519380, 16322298, 9738975, 12792784, 16000567, 8336941, 10753186, 9546439, 8062826, 11429705, 30840781, 15510160, 29922827, 9407971, 17606709, 21343334, 30720243, 29752319, 10864200, 29092957, 17311302, 32658383, 16861262, 21484931, 21552135, 8649776, 17540308, 15161705, 27813088, 15037740, 11793474, 9242456, 30224644, 26619011, 20693561, 12826609, 1565144, 29979965, 26014290) -
Brainstem glioma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Li-Fraumeni syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Multiple myeloma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 24, 2022- -
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Small cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Medulloblastoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Metastatic pancreatic neuroendocrine tumours Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchGenome Sciences Centre, British Columbia Cancer AgencyNov 01, 2017- -
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Uterine carcinosarcoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
B-cell chronic lymphocytic leukemia Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Neoplasm of ovary Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchGerman Consortium for Hereditary Breast and Ovarian Cancer, University Hospital CologneDec 01, 2018- -
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Uncertain
26
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.85
D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-6.5
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4
0.95
MutPred
0.99
Loss of disorder (P = 0.0542);.;.;.;.;.;.;.;Loss of disorder (P = 0.0542);.;Loss of disorder (P = 0.0542);Loss of disorder (P = 0.0542);Loss of disorder (P = 0.0542);.;.;Loss of disorder (P = 0.0542);.;.;.;
MVP
1.0
MPC
0.42
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28934576; hg19: chr17-7577120; COSMIC: COSV52664805; COSMIC: COSV52664805; API