rs535274413

Variant names:

• chr17-7676567-C-A
• rs535274413
• NM_000546.6:c.28G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7676567-C-A
• chr17-7676567-C-G
• chr17-7676567-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000546.6(TP53):​c.28G>T​(p.Val10Phe) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.419

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22428516).
• BP6: Variant 17-7676567-C-A is Benign according to our data. Variant chr17-7676567-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 968647.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.28G>T	p.Val10Phe	missense_variant	Exon 2 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.28G>T	p.Val10Phe	missense_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2

Feb 24, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with phenylalanine at codon 10 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). This variant did not impact function in yeast transactivation assays (PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). This variant has not been reported in individuals affected with hereditary cancer 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. -

Jul 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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: 968647). This missense change has been observed in individual(s) with cancer (PMID: 27545002). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 10 of the TP53 protein (p.Val10Phe). -

Hereditary cancer-predisposing syndrome Benign:1

Jun 12, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	9.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T;T;.;.;.;T;.;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Uncertain	0.92	D;D;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.55	.;.;N;N;N;N;N;.;.;.;.;.
PROVEAN	Benign	-0.69	N;N;N;.;N;N;N;.;N;N;.;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D;D;D;.;D;D;D;.;D;D;.;D
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;.;.;T;.
Polyphen		0.85	P;.;B;B;P;B;B;.;B;P;.;.
Vest4		0.29
MutPred		0.39		Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);Gain of glycosylation at P8 (P = 0.0918);
MVP		0.85
MPC		1.3
ClinPred		0.30	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.23

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: rs535274413; hg19: chr17-7579885;