rs121913343

Variant names:

• chr17-7673803-G-A
• rs121913343
• NM_000546.6:c.817C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7673803-G-A
• chr17-7673803-G-C
• chr17-7673803-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000187024: Studies conducted in human cell lines indicate this variant 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).; SCV005901780: Transactivation assays show a non-functional allele according to Kato 2003 (PMID:12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID:30224644) (PS3).; SCV000840079: Functional data showed that this variant leads to a severe deficiency of TP53 activity [PMID 21343334, 24677579, 17606709].; SCV004047202: 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).; SCV004933848: Functional studies indicate this variant impacts protein function [PMID:8001119, 16861262, 9482117].; SCV000060191: "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)"; SCV000261042: Experimental studies have shown that this missense change affects TP53 function (PMID:12826609, 20128691, 24677579, 29979965, 30224644).; SCV003934643: 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).; SCV000211760: 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); SCV006325616: Functional studies have shown that this missense change impacts TP53 activity (PMID:2012869, 24677579, 17606709).; SCV005350608: This variant has been shown to decrease protein function (Monti et al 2011. PubMed ID: 21343334).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R273S) has been classified as Uncertain significance.

• 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:26 U:1 O:9
• Conservation: PhyloP100: 5.73
• Publications: 1244 publications found

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]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000187024: Studies conducted in human cell lines indicate this variant 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).; SCV005901780: Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3).; SCV000840079: Functional data showed that this variant leads to a severe deficiency of TP53 activity [PMID 21343334, 24677579, 17606709].; SCV004047202: 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).; SCV004933848: Functional studies indicate this variant impacts protein function [PMID: 8001119, 16861262, 9482117].; SCV000060191: "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)"; SCV000261042: Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 24677579, 29979965, 30224644).; SCV003934643: 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).; SCV000211760: 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); SCV006325616: Functional studies have shown that this missense change impacts TP53 activity (PMID: 2012869, 24677579, 17606709).; SCV005350608: This variant has been shown to decrease protein function (Monti et al 2011. PubMed ID: 21343334).
• PM1: In a hotspot region, there are 64 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 26 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 VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 43594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.817C>T	p.Arg273Cys	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.817C>T	p.Arg273Cys	missense	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.817C>T	p.Arg273Cys	missense	Exon 9 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.817C>T	p.Arg273Cys	missense	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.817C>T	p.Arg273Cys	missense	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.700C>T	p.Arg234Cys	missense	Exon 7 of 10	ENSP00000478219.1	P04637-4

Frequencies

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

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

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250850 AF XY: 0.0000147

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000225653), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000781 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Li-Fraumeni syndrome 1 (7)
6	-	-	not provided (6)
4	-	-	Li-Fraumeni syndrome (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Adrenocortical carcinoma, hereditary (2)
2	-	-	TP53-related disorder (2)
1	-	-	Multiple myeloma (1)
1	-	-	Ovarian neoplasm (1)
-	1	-	Prostate cancer (1)
-	-	-	Adenocarcinoma of the large intestine (1)
-	-	-	Astrocytoma IDH-mutant (1)
-	-	-	Diffuse midline glioma, H3 K27M-mutant (1)
-	-	-	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1)
-	-	-	Embryonal rhabdomyosarcoma (1)
-	-	-	Medulloblastoma WNT activated (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.99		Loss of MoRF binding (P = 0.0762)
MVP		1.0
MPC		0.44
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.0032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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