rs876658916

chr17-7674184-G-Achr17-7674184-G-Cchr17-7674184-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000546.6(TP53):c.779C>T(p.Ser260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S260Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 4 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.779C>T	p.Ser260Phe	missense_variant	7/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.779C>T	p.Ser260Phe	missense_variant	7/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

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

Oct 05, 2023

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 260 of the TP53 protein (p.Ser260Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.026
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.46	T;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;T;D;T;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0090	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.073	B;.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4		0.54
MutPred		0.42		Loss of disorder (P = 0.0097);Loss of disorder (P = 0.0097);.;.;.;.;.;.;.;Loss of disorder (P = 0.0097);.;Loss of disorder (P = 0.0097);Loss of disorder (P = 0.0097);Loss of disorder (P = 0.0097);.;.;Loss of disorder (P = 0.0097);.;.;.;
MVP		0.97
MPC		0.11
ClinPred		0.81	D
GERP RS		4.5
Varity_R		0.86
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7577502; COSMIC: COSV52661443; COSMIC: COSV52661443;