17-7673775-C-G

Position:

• chr17-7673775-C-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.845G>C​(p.Arg282Pro) 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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.00

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 (HGNC:):

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, 0.988
• PP5: Variant 17-7673775-C-G is Pathogenic according to our data. Variant chr17-7673775-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.845G>C	p.Arg282Pro	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.845G>C	p.Arg282Pro	missense_variant	8/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2023	This missense variant replaces arginine with proline at codon 282 in the DNA binding domain of the TP53 protein. Computational prediction tool 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 that this variant impairs TP53 protein function. The mutant protein has been shown to be non-functional in yeast transactivation assays (PMID: 12826609), human cell growth suppression assays (PMID: 30224644) and human cell proliferation assay (PMID: 29979965). This variant has been reported in an individual affected with bone cancer at age 29, breast cancer at age 50, with family history of skin cancer, leukemia, cerebral tumor and Hodgkin lymphoma (PMID: 27616075); a female individual who was affected with breast and ovarian cancer in her twenties, with family history of early-onset breast cancer in the first and second degree relatives (Color Health internal data); as well as in a cohort with Li-Fraumeni syndrome and non-small-cell lung carcinoma (DOI:https://doi.org/10.1016/j.annonc.2022.07.1809). This variant has also been detected de novo in the germline of a female individual who was affected with choroid plexus carcinoma at age 17 and breast sarcoma at age 24 (PMID: 28369373, 29070607). 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	Oct 29, 2019	The p.R282P variant (also known as c.845G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 845. The arginine at codon 282 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in a German individual diagnosed with bone cancer at age 29 and breast cancer at age 50 and whose family history consisted of skin cancer, leukemia, cerebral tumors, and Hodgkin lymphoma (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102). This alteration has been reported in a female patient with choroid plexus carcinoma diagnosed at 17 and a breast sarcoma diagnosed at 24 (Zerdoumi Y et al. Hum. Mol. Genet., 2017 Mar). Further, Zerdoumi et al. conducted a functional assay in lymphocytes from this individual and showed a drastic reduction in p53 transcriptional activity similar to that observed in well characterized dominant-negative missense mutations. The p.R282P variant is located in the functionally critical DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression in vitro (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Two other alterations (p.R282W and p.R282G) have been described in the same codon in families meeting criteria for Li-Fraumeni syndrome (LFS) or suspected of having LFS (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 the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 21, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28472496, 27616075, 29070607]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2022

For these reasons, this variant has been classified as Pathogenic. 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, 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376659). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 27616075, 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 282 of the TP53 protein (p.Arg282Pro). -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 10, 2021

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
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	0.59	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
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.91
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	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.95
MutPred		0.91		Gain of glycosylation at R282 (P = 0.0343);.;.;.;.;.;.;.;Gain of glycosylation at R282 (P = 0.0343);.;Gain of glycosylation at R282 (P = 0.0343);Gain of glycosylation at R282 (P = 0.0343);Gain of glycosylation at R282 (P = 0.0343);.;.;Gain of glycosylation at R282 (P = 0.0343);.;.;.;
MVP		0.97
MPC		0.45
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.92

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: rs730882008; hg19: chr17-7577093; COSMIC: COSV52773873; COSMIC: COSV52773873;