rs1064794810

chr17-7673558-C-Achr17-7673558-C-Gchr17-7673558-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000546.6(TP53):c.970G>T(p.Asp324Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D324H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.970G>T	p.Asp324Tyr	missense_variant	9/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.970G>T	p.Asp324Tyr	missense_variant	9/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Uncertain	0.018	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		0.56
MutPred		0.61		Loss of ubiquitination at K321 (P = 0.0255);.;.;.;.;.;.;.;Loss of ubiquitination at K321 (P = 0.0255);.;Loss of ubiquitination at K321 (P = 0.0255);Loss of ubiquitination at K321 (P = 0.0255);Loss of ubiquitination at K321 (P = 0.0255);.;.;Loss of ubiquitination at K321 (P = 0.0255);.;.;.;
MVP		0.98
MPC		0.42
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.76

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: rs1064794810; hg19: chr17-7576876;