rs1060501200

chr17-7674903-T-Achr17-7674903-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000546.6(TP53):c.628A>T(p.Asn210Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. N210S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.858

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 15 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3857177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.628A>T	p.Asn210Tyr	missense_variant	6/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.628A>T	p.Asn210Tyr	missense_variant	6/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461892 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2016

In summary, this variant is a rare missense change that has been shown not to affect protein function in vitro. While it is absent from the population and reported in an affected individual, a pathogenic allele in a different gene was also identified in this same individual. The available evidence is currently insufficient to determine this variant's role in disease and therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies of transcriptional activity in yeast using a variety of different promoters indicate that this missense change does not impact TP53 function (PMID: 12826609, 21343334). This variant has been reported in the germline of an individual affected with familial adenomatous polyposis (FAP), however this same individual also carried a pathogenic allele in the APC gene (PMID: 11263856). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 210 of the TP53 protein (p.Asn210Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	17
Dann	Benign	0.24
DEOGEN2	Benign	0.42	T;T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.81	T;T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.16	B;.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B
Vest4		0.49
MutPred		0.75		Gain of phosphorylation at N210 (P = 0.0229);Gain of phosphorylation at N210 (P = 0.0229);.;.;.;.;.;.;.;Gain of phosphorylation at N210 (P = 0.0229);.;Gain of phosphorylation at N210 (P = 0.0229);Gain of phosphorylation at N210 (P = 0.0229);Gain of phosphorylation at N210 (P = 0.0229);.;.;Gain of phosphorylation at N210 (P = 0.0229);.;.;.;.;
MVP		0.92
MPC		0.92
ClinPred		0.080	T
GERP RS		-1.5
Varity_R		0.29
gMVP		0.38

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: rs1060501200; hg19: chr17-7578221;