17-7676157-G-C

Variant names:

• chr17-7676157-G-C
• rs878854065
• NM_000546.6:c.212C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000546.6(TP53):​c.212C>G​(p.Pro71Arg) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P71A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.302
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12626776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.212C>G	p.Pro71Arg	missense_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.212C>G	p.Pro71Arg	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

May 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with arginine at codon 71 of the TP53 protein (p.Pro71Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 237943). Experimental studies have shown that this missense change impairs binding of TP53 to its co-repressor Sin3, which may reduce TP53 protein stability (PMID: 11359905).  Studies are conflicting regarding the effect of this variant on TP53 transactivation: one study indicates that it has no effect, while another suggests that it partially reduces TP53 function (PMID: 11359905, 12826609). The clinical significance of these findings is unknown. In summary, this is a novel missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	5.4
DANN	Benign	0.82
DEOGEN2	Benign	0.019	T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.85	T;T;.;.;.;T;T;.;T;D;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.7	.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.
PhyloP100		0.30
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.67	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D;D;.;D;.;.;D;D;.;.;D;.;.;T;.;T
Sift4G	Benign	0.070	T;T;T;T;T;T;T;T;D;D;T;T;T;.;T;.
Polyphen		0.24	B;.;.;B;.;B;B;B;.;.;B;.;.;P;.;.
Vest4		0.21
MutPred		0.25		Loss of catalytic residue at P71 (P = 0.0356);Loss of catalytic residue at P71 (P = 0.0356);.;Loss of catalytic residue at P71 (P = 0.0356);.;Loss of catalytic residue at P71 (P = 0.0356);Loss of catalytic residue at P71 (P = 0.0356);Loss of catalytic residue at P71 (P = 0.0356);.;.;Loss of catalytic residue at P71 (P = 0.0356);.;Loss of catalytic residue at P71 (P = 0.0356);Loss of catalytic residue at P71 (P = 0.0356);Loss of catalytic residue at P71 (P = 0.0356);Loss of catalytic residue at P71 (P = 0.0356);
MVP		0.80
MPC		0.74
ClinPred		0.11	T
GERP RS		-0.68
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.19

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

Other links and lift over

dbSNP: rs878854065; hg19: chr17-7579475;