17-7675149-T-C

Variant names:

• chr17-7675149-T-C
• rs772683278
• NM_000546.6:c.463A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000546.6(TP53):​c.463A>G​(p.Thr155Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T155P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.442
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 41 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 43 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 chr17-7675149-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2768025.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17622855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.463A>G	p.Thr155Ala	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.463A>G	p.Thr155Ala	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251290 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Oct 30, 2020

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. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Uncertain:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (rs772683278, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 155 of the TP53 protein (p.Thr155Ala). 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, 22046250). 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. ClinVar contains an entry for this variant (Variation ID: 458544). -

Li-Fraumeni syndrome 1 Uncertain:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 02, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate functional transactivation and retained growth suppression activities (Kato 2003, Bernard 2011, Kotler 2018, Giacomelli 2018); This variant is associated with the following publications: (PMID: 30224644, 12826609, 29979965, 28176830, 22046250, 27070704, 25801821, 24665023, 24729566, 26205736, 23845441, 19139070, 18415037, 25496518, 17903248, 1868473) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	5.9
DANN	Benign	0.60
DEOGEN2	Benign	0.29	T;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.80	T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.51	.;.;.;.;.;.;N;.;N;N;N;.;.;N;.;.;.;.;.
PhyloP100		-0.44
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.36	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.67	T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;T
Sift4G	Benign	0.94	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.080	B;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.
Vest4		0.14
MutPred		0.59		Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);.;.;.;.;Loss of phosphorylation at T155 (P = 0.0156);.;Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);.;.;Loss of phosphorylation at T155 (P = 0.0156);.;.;.;.;Loss of phosphorylation at T155 (P = 0.0156);
MVP		0.92
MPC		0.64
ClinPred		0.058	T
GERP RS		0.31
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.30
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs772683278; hg19: chr17-7578467; COSMIC: COSV52661985; COSMIC: COSV52661985;