rs121913343

chr17-7673803-G-Achr17-7673803-G-Cchr17-7673803-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):c.817C>T(p.Arg273Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,760 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 Likely 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 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1 O:1
• Conservation: PhyloP100: 5.73

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• 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, 0.991
• PP5: Variant 17-7673803-G-A is Pathogenic according to our data. Variant chr17-7673803-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673803-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.817C>T	p.Arg273Cys	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.817C>T	p.Arg273Cys	missense_variant	8/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152044 Hom.: 0 Cov.: 31 FAILED QC

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250850 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461760 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152044 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74256

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: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 20, 2024	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 9047394, 10864200]. Functional studies indicate this variant impacts protein function [PMID: 8001119, 16861262, 9482117]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R273C in TP53 (NM_000546.6) has previously been detected in multiple patients with Li-Fraumeni syndrome or Li-Fraumeni related cancers (Eeles et al, 1993). This missense variant causes the same amino acid change as a previously established pathogenic variant. Functional studies reveal that this variant leads to a severe deficiency of TP53 activity (Monti et al, 2011). Experimental studies have shown that this missense change disrupts the DNA-binding, transcriptional transactivation, and tumor suppressor activities of the TP53 protein (Malcikova et al, 2010). The p.R273C variant is observed in 1/18,372 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R273C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 273 of TP53 is conserved in all mammalian species. The nucleotide c.817 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 03, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 06, 2017	This c.817C>T (p.Arg273Cys) variant has previously been detected in multiple patients with Li-Fraumeni syndrome or Li-Fraumeni related cancers [PMID 8479749, 21535297, 21552135]. Functional data showed that this variant leads to a severe deficiency of TP53 activity [PMID 21343334, 24677579, 17606709]. The amino acid position 273 of the TP53 protein is a hot spot for pathogenic variants causing Li-Fraumeni syndrome: additional variants affecting the same amino acid at position 273 have been reported (p.Arg273Gly and p.Arg273His). This variant was observed in three heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/17-7577121-G-A). This variant is highly conserved in mammals and computer-based algorithms predict this p.Arg273Cys change to be deleterious. It is thus classified as pathogenic. The next generation sequencing (NGS) reads indicated a skewed mutant to reference allele ratio (about 25% mutant), which was confirmed by Sanger sequencing, indicating mosaicism in this sample. Mosaic somatic pathogenic variants in cancer related genes, including TP53, have been reported in DNA extracted from blood samples in aging populations [PMID 25426837, 25426838, 25326804]. While an increase risk for hematologic cancer was reported in these studies, the clinical significance of these somatic variants in blood is currently unclear. While this variant is a known disease-causing variant observed in patients with Li-Fraumeni syndrome, considering the age of this individual, this finding may result from a somatic event observed in aging process. Studies in another tissue sample such as a skin biopsy is thus suggested to help clarify the clinical significance of this change. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2023	Published functional studies demonstrate a damaging effect: loss of growth suppression and apoptotic activities and non-functional transactivation (Kato et al., 2003; Dearth et al., 2007; Malcikova et al., 2010; Monti et al., 2011; Li et al., 2014; Giacomelli et al., 2018; Kotler et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11370630, 11315715, 7732013, 28915719, 28527674, 29958926, 27374712, 29489754, 20128691, 16861262, 17606709, 21343334, 21535297, 8479749, 21552135, 24677579, 7887414, 10864200, 11494139, 12695689, 19556618, 20443677, 26681312, 28387325, 28840050, 28717136, 28975465, 30720243, 30092803, 30796655, 30093976, 30840781, 31278746, 31559875, 15510160, 12826609, 35273153, 31105275, 31447099, 29922827, 34906214, 30224644, 29979965, 33245408, 32817165) -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TP53: PS3, PM1, PM2, PP4, PS4:Supporting -

Li-Fraumeni syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 273 of the TP53 protein (p.Arg273Cys). This variant is present in population databases (rs121913343, gnomAD 0.005%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8479749, 17606709, 21535297, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43594). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 24677579, 29979965, 30224644). This variant disrupts the p.Arg273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 8164043, 8479749, 17606709, 18685109, 20693561, 21535297, 21552135, 25584008; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: TP53 c.817C>T (p.Arg273Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250850 control chromosomes. c.817C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Masciari_2011, Khincha_2019, Rana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function shows a severe decrease in promoter binding and transactivation capability ( Monti_2011, Malcikova_2010). The following publications have been ascertained in the context of this evaluation (PMID: 23612969, 21343334, 31212162, 31105275, 21552135, 20128691). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Arg273Cys variant in TP53 has been reported in >5 individuals with Li-Fraumeni syndrome (LFS) or LFS-associated tumors (Gonzalez 2009, Janavicius 2011, Masciari 2011, Park 2016, Chan 2018). It has also been identified in 0.005% (1/21592) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43594). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies provide some evidence that this variant impacts/does not impact protein function (Thukral 1994, Kato 2003, Monti 2011, Li 2014) ; however, these types of assays may not accurately represent biological function. An additional variant involving this codon (p.Arg273Leu) has been identified in individuals with LFS and is classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PS4, PM5, PS3_Moderate, PM2_Supporting, PP3. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2021	The p.R273C pathogenic mutation (also known as c.817C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 817. The arginine at codon 273 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple families that met classic LFS or Chompret criteria (Janaviius R et al. Breast J. 2011;17(4):409-415; Masciari S et al. Genet. Med. 2011 Jul;13(7):651-7). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative phenotype (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; 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 position is characterized as a mutation hotspot and has been shown to be involved in DNA contact and binding (Martin AC et al. Hum. Mutat. 2002 Feb;19(2):149-64). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2023

- -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

-

- -

Breast neoplasm Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	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	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.95
MutPred		0.99		Loss of MoRF binding (P = 0.0762);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0762);.;Loss of MoRF binding (P = 0.0762);Loss of MoRF binding (P = 0.0762);Loss of MoRF binding (P = 0.0762);.;.;Loss of MoRF binding (P = 0.0762);.;.;.;
MVP		1.0
MPC		0.44
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs121913343; hg19: chr17-7577121; COSMIC: COSV52662066; COSMIC: COSV52662066;