rs1555526625

Positions:

• chr17-7676100-G-A
• chr17-7676100-G-C
• chr17-7676100-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000546.6(TP53):​c.269C>T​(p.Ser90Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,684 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.09

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37674814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.269C>T	p.Ser90Phe	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.269C>T	p.Ser90Phe	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460684 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726616

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2017

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. An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant has not been reported in the literature in individuals with TP53-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 90 of the TP53 protein (p.Ser90Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2015

The p.S90F variant (also known as c.269C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 269. The serine at codon 90 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported as a somatic mutation 2 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). Functional studies show transactivation activity similar to wild type in yeast assays (IARC TP53 database: Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is poorly conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.S90F remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;.;D;.;.;.;.;.;.;D;.;.;T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.080	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D;D;.;T;.;.;T;T;.;.;T;.;.;D;.;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.
Polyphen		0.94	P;.;.;B;.;P;D;P;.;.;B;.;.;D;.;.
Vest4		0.31
MutPred		0.18		Loss of glycosylation at S90 (P = 0.0079);Loss of glycosylation at S90 (P = 0.0079);.;Loss of glycosylation at S90 (P = 0.0079);.;Loss of glycosylation at S90 (P = 0.0079);Loss of glycosylation at S90 (P = 0.0079);Loss of glycosylation at S90 (P = 0.0079);.;.;Loss of glycosylation at S90 (P = 0.0079);.;Loss of glycosylation at S90 (P = 0.0079);Loss of glycosylation at S90 (P = 0.0079);Loss of glycosylation at S90 (P = 0.0079);Loss of glycosylation at S90 (P = 0.0079);
MVP		0.89
MPC		1.4
ClinPred		0.48	T
GERP RS		3.0
Varity_R		0.17
gMVP		0.36

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: rs1555526625; hg19: chr17-7579418; COSMIC: COSV52787750; COSMIC: COSV52787750;