rs55832599

chr17-7673821-G-Achr17-7673821-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):c.799C>T(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,072 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. R267Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 2.31

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 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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 chr17-7673821-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1761541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-7673821-G-A is Pathogenic according to our data. Variant chr17-7673821-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673821-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.799C>T	p.Arg267Trp	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.799C>T	p.Arg267Trp	missense_variant	8/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461072 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726772

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2022	Variant summary: TP53 c.799C>T (p.Arg267Trp) results in a non-conservative amino acid change located in the p53, 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 was absent in 248996 control chromosomes (gnomAD). c.799C>T has been reported in the literature in individuals affected with Li-Fraumeni Syndrome and various types of cancer (examples: Villani_2016, llovet_2017, Stoltze_2018, AlHarbi_2018, Fortuno_2019, and Rana_2019). However, it has also been reported in unaffected individuals including one homozygote, reflecting possible lower penetrance of the variant (examples: AlHarbi_2018 and Stoltze_2018). Multiple publications have reported that this variant impairs the normal activity of the protein (examples: Wang_2014 and Dearth_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Feb 28, 2020	Data included in classification: UK family 1: Proband breast cancer at 42, mother breast cancer at 62 and melanoma, confirmed heterozygous for variant, maternal aunt leukaemia 30s, another maternal aunt colorectal ca 66 and lung ca 77, maternal grandmother lung ca 74 and maternal grandfather brain tumour (meets Chompret criteria). Literature family 1: MDS at 52, breast fibroadenoma, melanoma in situ, sessile serrated adenoma, subependymoma (all in 50s) (Villani et al, 2017, PMID: 27501770). Literature family 2: proband breast cancer at 31 and soft tissue sarcoma at 43, relative with breast cancer at 34 (meets Chompret criteria) (Lovett et al, 2017, PMID:28573494). Literature family 3: proband breast cancer at 43, sibling with oligodendroglioma at 31yrs (Stoltz et al, 2018, PMID:29324801) Literature family 4: AlHarbi et al 2018 (PMID: 30588330) proband CPC at 2, sister CPC at 14 months, paternal aunt (heterozygous for variant) liver cancer at 49, paternal great uncle CRC at 55, paternal great aunt and great grandmother brain tumours (meets Chompret criteria) (PS4_mod). Absent from gnomAD (PM2_sup). Deleterious on SIFT, Polyphen, AlignGVGD, Bayesdel 0.542, Revel 0.917 (PP3_mod). Functional data: Non-functional on Kato et al, 2003(PMID: 12826609); impaired function on Fulci et al, 2002: PMID: 12019170), Wang et al, 2013 (PMID: 24076587), Perez et al, 2016 (PMID: 27022024) (PS3_strong). Additional data (not included in classification): 5 classifications of likely pathogenic on ClinVar. Unaffected 38 year old homozygote (AlHarbi et al, 2018, PMID: 30588330). Wang et al, 2013 (PMID:23484829): variant reported but no family information available. AlHarbi et al 2018 (Stoltz et al, 2018 (PMID: 29324801) variant segregates with multiple relatives with cancer diagnoses, but also with unaffected relatives. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 267 of the TP53 protein (p.Arg267Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 27501770, 28573494, 29324801, 30588330). ClinVar contains an entry for this variant (Variation ID: 141764). 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, 16861262, 24076587). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965). This variant has been reported in individuals affected with early-onset breast cancer, glioma, and soft-tissue sarcoma, who meet the Chompret criteria for Li-Fraumeni syndrome (PMID: 28573494, 2932480, 34240179, Color internal data). This variant has also been reported in an unaffected individual with family history of Li-Fraumeni syndrome (PMID: 23484829). In one family meeting the Chompret criteria for Li-Fraumeni syndrome, this variant was observed in two heterozygous siblings affected with choroid plexus carcinomas and in their homozygous father who was healthy at age 39, indicating possibly low or variable penetrance of this variant (PMID: 30588330). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals that meet the criteria for Li-Fraumeni syndrome (LFS) (PMID: 30588330 (2018), 29324801 (2018), 28573494 (2017)). The variant is reported in individuals with breast cancer (PMID: 34240179 (2021), 33471991 (2021), 30287823 (2018), 29324801 (2018), 28573494 (2017), 21761402 (2012)), melanoma (31567591 (2020)), choroid plexus carcinoma (30588330 (2018)), liver cancer (30588330 (2018)), and myelodysplastic syndrome 27501770 (2016). Additionally, this variant is found in heterozygous and homozygous states in unaffected individuals with a family history of LFS (PMID: 30588330 (2018), 23484829 (2013)). Functional studies have found this variant impairs transcriptional activity, DNA binding, and apoptosis (PMID: 24076587 (2014), 16861262 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 09, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2023	Observed in individuals with Li-Fraumeni-related and other cancers, but also present in unaffected individuals, with one unaffected homozygous adult reported (PMID: 21761402, 27501770, 28573494, 29085664, 30588330, 29324801, 35974385, 37377903); Published functional studies demonstrate a damaging effect: non-functional or decreased transactivation, and decreased or wildtype-like growth suppression activity (PMID: 9627118, 12826609, 16861262, 21232794, 25831048, 30224644, 29979965); 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: 27492616, 27022024, 21761402, 23484829, 15580553, 24868540, 26205736, 23536279, 22037554, 25171927, 26682952, 26342236, 26467027, 28445466, 28161563, 28915717, 29472312, 29515972, 16959974, 17311302, 12019170, 16941491, 19954513, 21060032, 24076587, 25831048, 18555592, 10557074, 12124823, 16322298, 27501770, 16861262, 9627118, 24164297, 21159888, 22205265, 25801821, 12934086, 9580667, 21232794, 12826609, 28446506, 28573494, 29085664, 17606709, 19367569, 21343334, 1562462, 30720243, 30840781, 31775759, 30588330, 29324801, 29805648, 31105275, 29979965, 31567591, 32817165, 32164171, 32832836, 30224644, 34240179, 35483880, 33153497, 37377903, 35974385, 37622400, 34273903, 33471991, 22915647, 27276561, 16818505, 11782540, 27959731, 23246812, 20407015, 22186996, 21519010, 26585234, 25952993, 27463065, 27680515, 30327374, 27895058, 37715966, 37327320, 15510160, 36703617, 36113475, 36628428, 37306523) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 03, 2023	This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965). This variant has been reported in individuals affected with early-onset breast cancer, glioma, and soft-tissue sarcoma, who meet the Chompret criteria for Li-Fraumeni syndrome (PMID: 28573494, 2932480, 34240179, Color internal data). This variant has also been reported in an unaffected individual with family history of Li-Fraumeni syndrome (PMID: 23484829). In one family meeting the Chompret criteria for Li-Fraumeni syndrome, this variant was observed in two heterozygous siblings affected with choroid plexus carcinomas and in their homozygous father who was healthy at age 39, indicating possibly low or variable penetrance of this variant (PMID: 30588330). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	The p.R267W variant (also known as c.799C>T) is located in coding exon 7 of the TP53 gene. This alteration results from a C to T substitution at nucleotide position 799. The arginine at codon 267 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in breast cancer patients (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13; Stoltze U et al. PLoS ONE, 2018 Jan;13:e0190050; Dorling et al. N Engl J Med. 2021 02;384:428-439) and in a female patient with myelodysplastic syndrome at age 52 (Villani A et al. Lancet Oncol., 2016 Sep;17:1295-305). It was also identified in two members of one family that met Li-Fraumeni syndrome (LFS) criteria (Llovet P et al. Fam. Cancer. 2017 Oct;16(4):567-575), in two siblings with choroid plexus carcinomas (AlHarbi M et al. NPJ Genom Med. 2018 Dec 19;3:35) and additional families with attenuated or classic LFS phenotypes (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a moderate dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional functional assays conducted in human tumor cell lines demonstrated a lack of transactivation activity, deficient DNA binding, and an inability to suppress cell growth in response to DNA damaging agents (Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32; Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8). To date, this alteration has not been detected in any cases of classic Li-Fraumeni syndrome (LFS) in our clinical cohort (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R267W is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 20, 2024	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24076587, 27022024, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28573494, 29324801]. -

Adrenocortical carcinoma, hereditary Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 15, 2021

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Lip and oral cavity carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
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	0.68	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	0.94	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.4	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	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		0.98, 0.97, 1.0	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.98
MutPred		0.91		Loss of disorder (P = 0.0012);.;.;.;.;.;.;.;Loss of disorder (P = 0.0012);.;Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);.;.;Loss of disorder (P = 0.0012);.;.;.;
MVP		0.99
MPC		0.28
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs55832599; hg19: chr17-7577139; COSMIC: COSV52678166; COSMIC: COSV52678166;