17-7676050-A-T

Position:

• chr17-7676050-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000546.6(TP53):​c.319T>A​(p.Tyr107Asn) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Required for interaction with ZNF385A (size 200) in uniprot entity P53_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.319T>A	p.Tyr107Asn	missense_variant	4/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.319T>A	p.Tyr107Asn	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2016

This sequence change replaces tyrosine with asparagine at codon 107 of the TP53 protein (p.Tyr107Asn). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and asparagine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D;.;D;.;.;.;.;.;.;D;.;.;D;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.
Polyphen		0.99	D;.;.;D;.;D;D;D;.;.;D;.;.;D;.;.
Vest4		0.61
MutPred		0.77		Gain of disorder (P = 0.0349);Gain of disorder (P = 0.0349);.;Gain of disorder (P = 0.0349);.;Gain of disorder (P = 0.0349);Gain of disorder (P = 0.0349);Gain of disorder (P = 0.0349);.;.;Gain of disorder (P = 0.0349);.;Gain of disorder (P = 0.0349);Gain of disorder (P = 0.0349);Gain of disorder (P = 0.0349);Gain of disorder (P = 0.0349);
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368771578; hg19: chr17-7579368;