17-7670613-A-G

Position:

• chr17-7670613-A-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.1096T>C​(p.Ser366Pro) 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. 12/21 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. S366A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.669

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 region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 512 pathogenic changes around while only 124 benign (81%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28121388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1096T>C	p.Ser366Pro	missense_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1096T>C	p.Ser366Pro	missense_variant	10/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Breda Genetics srl

Oct 19, 2022

The variant c.1096T>C (p.Ser366Pro) in the TP53 gene is reported as uncertain significance for the Li-Fraumeni in ClinVar (Variation ID: 528252). There is no information on frequency in gnomAD or 1000 Genomes Project. The nucleotide position is weakly conserved across 35 mammalian species (GERP RS: 1.77). In silico analysis mostly indicates that the variant might be neutral. However, especially in the setting of variable expressivity, it is advised to use in silico prediction tools with caution (PMID: 29805046).The variant falls within a codon of the TP53 gene which is not reported as hot spot codon for cancer in the TP53 National Cancer Institute (NCI) database of the National Institutes of Health, as defined by Chang et al. (2017, PMID: 29069792). Another missense variant at the same nucleotide position c.1096T>G (p.Ser366Ala) has been reported in ClinVar (variation ID: 135360) and in the Global Variome shared LOVD v.3.0 database and in the UMD TP53 mutation database as likely benign. -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2022

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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 528252). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 366 of the TP53 protein (p.Ser366Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;.;.;T;.;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.60	T;T;.;.;.;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.4	.;.;.;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.24	.;.;.;N;.;N;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.045	.;.;.;D;.;D;.;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T
Polyphen		0.0010	.;.;.;B;.;B;.;.
Vest4		0.28
MutPred		0.17		.;.;.;Loss of phosphorylation at S366 (P = 0.0028);.;Loss of phosphorylation at S366 (P = 0.0028);.;.;
MVP		0.76
MPC		0.079
ClinPred		0.11	T
GERP RS		1.8
Varity_R		0.22
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

LitVar

Other links and lift over

dbSNP: rs17881470; hg19: chr17-7573931;