17-7673776-G-C

Variant names:

• chr17-7673776-G-C
• rs28934574
• NM_000546.6:c.844C>G

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.844C>G​(p.Arg282Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R282Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.02

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 region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) 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 chr17-7673775-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-7673776-G-C is Pathogenic according to our data. Variant chr17-7673776-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 140821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.844C>G	p.Arg282Gly	missense_variant	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.844C>G	p.Arg282Gly	missense_variant	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Jun 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.844C>G (p.Arg282Gly) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). c.844C>G has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) and tumors belonging to the LFS spectrum (e.g. Poli_2005, Bougeard_2008, Schrader_2016, Rana_2019, Ceyhan-Birsoy_2021). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.844C>T, p.R282W), supporting the critical relevance of codon 282 to TP53 protein function. Multiple publications also reported experimental evidence and demonstrated the variant to be non-functional based on transcriptional activity in yeast, and substantially affecting TP53 function in human cell lines (e.g. Kato_2003, Monti_2011, Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 15850016, 18511570, 26556299, 31105275, 34240179, 12826609). ClinVar contains an entry for this variant (Variation ID: 140821). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 282 of the TP53 protein (p.Arg282Gly). 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: 15850016, 26014290, 26556299, 28802053). ClinVar contains an entry for this variant (Variation ID: 140821). 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, 21343334, 23246812, 29979965, 30224644). This variant disrupts the p.Arg282 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 1565144, 11370630, 12826609, 17606709, 19468865, 21305319, 21761402, 22672556, 25584008). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R282G pathogenic mutation (also known as c.844C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 844. The arginine at codon 282 is replaced by glycine, an amino acid with dissimilar properties. This mutation is in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). It was previously identified in a patient with primary orbital liposarcoma whose family met diagnostic criteria for Li-Fraumeni syndrome (LFS) (Poli T et al. Tumori; 91:96-100). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Additionally, two other missense mutations occurring at the same codon have been reported (p.R282Q and p.R282W). In one study, the p.R282Q mutation was reported in a 14-year-old male with a soft tissue sarcoma who was later diagnosed with an osteosarcoma and lung cancer (Chompret et al. 2000 British J Cancer 82(12):1932-1937). The p.R282W mutation was detected in a patient with contralateral breast cancer at age 32 (Heyman et al. 2010 Radiation Oncology 5:104), and in a kindred with clinical LFS, however, specific clinical information was not provided (Wu et al. 2011 Hum Genet 129:663-673). Based on the supporting evidence, the p.R282G alteration is interpreted as a disease-causing mutation. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1 Pathogenic:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Monti et al., 2003; Ferrone et al., 2006; Giacomelli et al., 2018; Kotler et al., 2018); Observed in individuals with TP53-related tumors (Bougeard et al., 2015; Pelttari et al., 2017; Rana et al., 2019; Gao et al., 2020); 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: 21343334, 22672556, 21761402, 21059199, 26619011, 25584008, 29979965, 11370630, 16818505, 12826609, 21305319, 12917626, 30224644, 1565144, 15850016, 23246812, 19468865, 17606709, 1565143, 15510160, 26556299, 30840781, 31105275, 32817165, 26014290, 22768918, 30720243, 28802053, 25847421) -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	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	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.86, 0.83, 1.0	.;.;.;.;.;.;.;.;P;.;P;D;P;.;.;P;.;.;.
Vest4		0.93
MutPred		0.97		Gain of catalytic residue at P278 (P = 0.1082);.;.;.;.;.;.;.;Gain of catalytic residue at P278 (P = 0.1082);.;Gain of catalytic residue at P278 (P = 0.1082);Gain of catalytic residue at P278 (P = 0.1082);Gain of catalytic residue at P278 (P = 0.1082);.;.;Gain of catalytic residue at P278 (P = 0.1082);.;.;.;
MVP		0.99
MPC		0.15
ClinPred		1.0	D
GERP RS		1.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.99
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs28934574; hg19: chr17-7577094; COSMIC: COSV52701296; COSMIC: COSV52701296;