17-7675131-C-T

Position:

• chr17-7675131-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000546.6(TP53):​c.481G>A​(p.Ala161Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A161D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 0.796

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7675130-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422295.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 17-7675131-C-T is Pathogenic according to our data. Variant chr17-7675131-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.481G>A	p.Ala161Thr	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.481G>A	p.Ala161Thr	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29456621]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 18, 2020	The TP53 c.481G>A (p.Ala161Thr) missense variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). It is located in a mutational hotspot defined as ≥ 10 somatic occurrences (PM1; cancerhotspots.org). The variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 55 (PP3). Additionally, transactivation assays show a partially functioning allele according to Kato et al., and there is evidence of a dominant negative effect and loss of function according to Giacomelli et al. (PS3_Moderate; PMID 12826609, 30224644). This variant has been reported in one family meeting classic Li-Fraumeni syndrome criteria (PMID: 29456621). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1: PM2_Supporting, PM1, PP3, PS3_Moderate. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2022	The p.A161T pathogenic mutation (also known as c.481G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 481. The alanine at codon 161 is replaced by threonine, an amino acid with similar properties. This variant has been observed in multiple families with clinical histories consistent with a diagnosis of Li-Fraumeni syndrome (LFS) (Freitas AC et al. Ecancermedicalscience. 2018 Jan;12:804; Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and 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 a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2023	This missense variant replaces alanine with threonine at codon 161 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is partially functional in yeast transactivation assays and showed temperature-sensitive defects (PMID: 11222779, 12826609, 21232794). This variant exhibited dominant negative effect and loss of function in human cell growth suppression assays and was non-functional in a human cell proliferation assay (PMID: 29979965, 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome, breast cancer, and chronic lymphocytic leukemia (PMID: 21232794, 26681312, 29456621). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 161 of the TP53 protein (p.Ala161Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 26681312, 29456621; Invitae). ClinVar contains an entry for this variant (Variation ID: 161518). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 11222779, 12826609, 16827139, 21232794, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 06, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2021

Published functional studies demonstrate a damaging effect: partial transactivation activity and a dominant negative effect (Kato 2003, Giacomelli 2018, Kotler 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26681312, 14559903, 11222779, 12532420, 9572492, 15580553, 21232794, 18818522, 12509970, 9627118, 16827139, 30720243, 30840781, 30213983, 30224644, 29456621, 29979965) -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G	Uncertain	0.013	D;D;T;T;D;D;T;T;D;D;D;D;D;D;D;D;D;D;D;T;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.
Vest4		0.57
MutPred		0.71		Gain of phosphorylation at A161 (P = 0.0564);Gain of phosphorylation at A161 (P = 0.0564);.;.;.;.;.;.;.;Gain of phosphorylation at A161 (P = 0.0564);.;Gain of phosphorylation at A161 (P = 0.0564);Gain of phosphorylation at A161 (P = 0.0564);Gain of phosphorylation at A161 (P = 0.0564);.;.;Gain of phosphorylation at A161 (P = 0.0564);.;.;.;.;Gain of phosphorylation at A161 (P = 0.0564);
MVP		0.94
MPC		1.6
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.59

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: rs193920817; hg19: chr17-7578449; COSMIC: COSV52660939; COSMIC: COSV52660939;