NM_000546.6:c.1010G>C

Variant names:

• chr17-7670699-C-G
• rs121912664
• NM_000546.6:c.1010G>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.1010G>C​(p.Arg337Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R337C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.244

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 HIPK1 (size 270) in uniprot entity P53_HUMAN there are 62 pathogenic changes around while only 6 benign (91%) 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 chr17-7670700-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 17-7670699-C-G is Pathogenic according to our data. Variant chr17-7670699-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177879.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.1010G>C	p.Arg337Pro	missense_variant	Exon 10 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1010G>C	p.Arg337Pro	missense_variant	Exon 10 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Apr 28, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R337P variant (also known as c.1010G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1010. The arginine at codon 337 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in a 5 year old patient with acute lymphoblastic leukemia and adrenocortical carcinoma, as well as several family members with cancer (Karakas Z et al. Pediatr Hematol Oncol, 2010 May;27:297-305). This variant is in the oligomerization domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays, and loss of tetramer formation in studies conducted in human cell lines (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Fischer NW et al. J. Natl. Cancer Inst., 2018 12;110:1418-1421). 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. -

Jan 14, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with proline at codon 337 in the tetramerization 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 that the mutant protein to be defective in tetramer formation (PMID: 19454241, 20978130, 29955864) and transactivation function (PMID: 10519380, 10719737, 12826609, 19454241, 29955864). This variant has been reported in three individuals affected with Li-Fraumeni syndrome (PMID: 2042652, 29955864). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same amino acid position, p.Arg337His, is known to be disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Pathogenic:2

Aug 13, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10864200, 16033918, 16494995, 21192060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609, 19454241, 29955864). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 20426520). ClinVar contains an entry for this variant (Variation ID: 177879). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 337 of the TP53 protein (p.Arg337Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Li-Fraumeni syndrome 1 Pathogenic:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;.;.;D;.;D;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;.;.;.;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.0	.;.;.;D;.;D;.;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	.;.;.;D;.;D;.;.
Sift4G	Uncertain	0.055	T;T;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;D;.;.
Vest4		0.85
MutPred		0.80		.;.;.;Loss of MoRF binding (P = 0.027);.;Loss of MoRF binding (P = 0.027);.;.;
MVP		0.99
MPC		0.45
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.99
gMVP		0.88

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: rs121912664; hg19: chr17-7574017; COSMIC: COSV52828545; COSMIC: COSV52828545;