rs587782148

Positions:

• chr17-7676113-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000546.6(TP53):​c.256G>A​(p.Ala86Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.440

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.085077584).
• BP6: Variant 17-7676113-C-T is Benign according to our data. Variant chr17-7676113-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141967.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.256G>A	p.Ala86Thr	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.256G>A	p.Ala86Thr	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460748 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726636

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2021	Published functional studies demonstrate functional transactivation and no dominant negative effect over wildtype (Marutani 1999, Kato 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Observed in an individual with malignant mesothelioma (De Rienzo 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 10519380, 27535533, 15510160, 26554828) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)) and in an individual with mesothelioma (PMID: 26554828 (2016)). Functional analysis has determined that this variant does not impact transactivation capacity and does not display a dominant negative effect (PMIDs: 10519380 (1999), 12826609 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 20, 2020	- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 86 of the TP53 protein (p.Ala86Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant pleural mesothelioma (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 141967). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 10519380, 12826609). 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	0.74
DANN	Benign	0.73
DEOGEN2	Benign	0.0034	T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.75	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.56	.;.;.;N;.;N;N;N;.;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.41	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.32	T;T;.;T;.;.;T;T;.;.;T;.;.;T;.;T
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.0030	B;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.
Vest4		0.11
MutPred		0.22		Gain of glycosylation at A86 (P = 0);Gain of glycosylation at A86 (P = 0);.;Gain of glycosylation at A86 (P = 0);.;Gain of glycosylation at A86 (P = 0);Gain of glycosylation at A86 (P = 0);Gain of glycosylation at A86 (P = 0);.;.;Gain of glycosylation at A86 (P = 0);.;Gain of glycosylation at A86 (P = 0);Gain of glycosylation at A86 (P = 0);Gain of glycosylation at A86 (P = 0);Gain of glycosylation at A86 (P = 0);
MVP		0.83
MPC		0.63
ClinPred		0.046	T
GERP RS		-2.7
Varity_R		0.053
gMVP		0.19

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: rs587782148; hg19: chr17-7579431; COSMIC: COSV105877899; COSMIC: COSV105877899;