rs779000871

chr17-7675103-G-Achr17-7675103-G-Cchr17-7675103-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 6P and 12B. PM1 PP3_Strong BP6_Very_Strong BS2

The NM_000546.6(TP53):c.509C>T(p.Thr170Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T170A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:6 B:3
• Conservation: PhyloP100: 8.16

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 -6 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000546.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• BP6: Variant 17-7675103-G-A is Benign according to our data. Variant chr17-7675103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184014.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAdExome at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.509C>T	p.Thr170Met	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.509C>T	p.Thr170Met	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251322 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74356

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 02, 2017	- -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Apr 12, 2021	This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.509C>T (p.Thr170Met) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS2_supporting; BS3_supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 11, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2022	This missense variant replaces threonine with methionine at codon 170 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 displays normal function in yeast transactivation and human growth suppression and cell proliferation studies (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with rhabdomyosarcoma and breast cancer in the literature (PMID: 22653678, 31081129). This variant has been identified in 13/282706 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2023	The p.T170M variant (also known as c.509C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 509. The threonine at codon 170 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a patient diagnosed with an embryonal rhabdomyosarcoma of the testes at age 5; however, the family history did not resemble Li-Fraumeni syndrome and the parents were unavailable for testing (Magnusson, S et al. Pediatr Blood Cancer. 2012 Nov;59(5):846-53). This alteration was also seen in a penile carcinoma genome and IHC results on the tumor were consistent with altered p53 protein (Rocha, RM et al. Hum Pathol. 2012 Apr;43(4):481-8). This alteration has also been reported in hereditary breast cancer and prostate cancer cohorts (Kharaziha P et al. Clin Genet, 2019 09;96:216-225; Rantapero T et al. Genes (Basel), 2020 03;11:) This variant is in the DNA binding domain of the p53 protein and is reported to have partially functional transactivation capacity and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no 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 amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 25, 2023	This missense variant replaces threonine with methionine at codon 170 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 displays normal function in yeast transactivation and human growth suppression and cell proliferation studies (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with rhabdomyosarcoma and breast cancer in the literature (PMID: 22653678, 31081129). This variant has been identified in 13/282706 chromosomes 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: intact growth suppression activity and partially functional transactivation (Kotler 2018, Kato 2003); Observed in individuals with breast cancer and rhabdomyosarcoma (Kharaziha 2019, Magnusson 2012); This variant is associated with the following publications: (PMID: 26001389, 29079180, 12826609, 15510160, 22653678, 16546179, 21925707, 25480502, 27311873, 29979965, 28861920, 31016814, 30840781, 14559903, 31081129) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.5	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;B;.;B;P;B;.;.;B;.;.;.;D
Vest4		0.40
MutPred		0.80		Gain of MoRF binding (P = 0.0847);Gain of MoRF binding (P = 0.0847);.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0847);.;Gain of MoRF binding (P = 0.0847);Gain of MoRF binding (P = 0.0847);Gain of MoRF binding (P = 0.0847);.;.;Gain of MoRF binding (P = 0.0847);.;.;.;.;
MVP		0.97
MPC		1.7
ClinPred		0.71	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.27

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: rs779000871; hg19: chr17-7578421; COSMIC: COSV52701457; COSMIC: COSV52701457;