17-7675148-G-T

Variant names:

• chr17-7675148-G-T
• rs786202752
• NM_000546.6:c.464C>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000546.6(TP53):​c.464C>A​(p.Thr155Asn) 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 1.20

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 14 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 17-7675148-G-T is Pathogenic according to our data. Variant chr17-7675148-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.464C>A	p.Thr155Asn	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.464C>A	p.Thr155Asn	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461882 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Jun 02, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.464C>A (p.Thr155Asn) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. In addition to being widely reported in a variety of somatic cancers, c.464C>A has been reported in the literature as a reportedly germline variant in settings of glioma and breast cancer and (example, Kyritsis_1994, Nandikolla_2017). At least one publication reports experimental evidence evaluating an impact on protein function (example, Kato_2003). The most pronounced variant effect results in non-functional outcome based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 155 of the TP53 protein (p.Thr155Asn). 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: 8308926, 28356770; internal data). ClinVar contains an entry for this variant (Variation ID: 406564). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:1

Feb 14, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:1

Jan 25, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation and dominant negative effect (Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with TP53-related cancers (Kyritsis 1994, Nandikolla 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29979965, 15510160, 26718964, 25149524, 15781632, 32850382, 30840781, 17606709, 21343334, 30224644, 28356770, 24113472, 8308926, 32321992, 30720243) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T155N pathogenic mutation (also known as c.464C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 464. The threonine at codon 155 is replaced by asparagine, an amino acid with similar properties. This alteration has been detected in several individuals meeting the revised Chompret criteria (Kyritsis A et al. J. Natl. Cancer Inst. 1994 Mar; 86(5):344-9; Nandikolla A et al. Breast Cancer (Dove Med Press) 2017; 9 207-215; Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have a loss of transactivation in yeast-based assays (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Smardova J et al. Oncol. Rep. 2016 Mar;35:1859-67). Studies conducted in human cell lines indicate this alteration has dominant-negative activity and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The threonine at codon 155 is a target of phosphorylation, which may be an important regulatory step for maintaining appropriate levels of p53 protein in the cell (Bech-Otschir D et al. EMBO J. 2001 Apr; 20(7):1630-9). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified Uncertain:1

Jan 19, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Uncertain	0.67	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Polyphen		0.95	P;.;.;.;.;.;B;.;P;B;P;.;.;B;.;.;.;P;.
Vest4		0.71
MutPred		0.89		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		0.87
MPC		1.5
ClinPred		0.64	D
GERP RS		-0.47
Varity_R		0.79
gMVP		0.45

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: rs786202752; hg19: chr17-7578466; COSMIC: COSV52711720; COSMIC: COSV52711720;