rs201753350

Positions:

• chr17-7676387-C-A
• chr17-7676387-C-G
• chr17-7676387-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000546.6(TP53):​c.91G>T​(p.Val31Phe) 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. 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. V31I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.909

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22983995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.91G>T	p.Val31Phe	missense_variant	3/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.91G>T	p.Val31Phe	missense_variant	3/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 06, 2023	This missense variant replaces valine with phenylalanine at codon 31 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies using yeast transcriptional transactivation assays demonstrated partial function while human cell growth suppression assays were inconclusive for this variant (PMID: 12826609, 30224644). This variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2023	The p.V31F variant (also known as c.91G>T), located in coding exon 2 of the TP53 gene, results from a G to T substitution at nucleotide position 91. The valine at codon 31 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. This variant is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 29, 2022	The TP53 c.91G>T (p.Val31Phe) missense change is absent in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in individuals meeting clinical criteria for Li-Fraumeni syndrome. Computational evidence supports a benign effect of this variant on protein function (Align GVGD = C0, BayesDel = 0.0291). Transactivation assays show a partially functioning allele according to Kato et al., and there is modest evidence of loss of function according to Giacomelli et al. but not a dominant negative effect (PMID 12826609, 30224644). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2022

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 31 of the TP53 protein (p.Val31Phe). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 233852). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.74	T;T;.;T;T;.;T;T;D;T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	.;.;L;L;L;L;L;.;.;.;.;.
PROVEAN	Benign	-1.1	N;N;N;.;N;N;N;.;N;N;.;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.010	D;D;D;.;D;D;D;.;D;D;.;D
Sift4G	Benign	0.16	T;T;T;T;T;T;T;T;.;.;D;.
Polyphen		0.80	P;.;B;P;P;P;B;.;B;P;.;.
Vest4		0.29
MutPred		0.34		Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);Loss of stability (P = 0.1466);
MVP		0.89
MPC		1.1
ClinPred		0.70	D
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.32
gMVP		0.46

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: rs201753350; hg19: chr17-7579705;