17-7673775-C-A

Position:

chr17-7673775-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_ModeratePM1BS3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant is absent from the gnomAD non-cancer v2.1.1 dataset (PM2_supporting). Transactivation assays show retained function according to Kato, et al (PMID:12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (PMID:30224644) (BS3). Additionally, this variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_moderate). Codon 282 is considered a hotspot (PM1) per the revised TP53 classification rules (PMID:33300245). In summary, TP53 c.845G>T; p.Arg282Leu meets criteria to be classified as uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting; PP3_moderate; PM1; BS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000456/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 6.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.845G>T	p.Arg282Leu	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.845G>T	p.Arg282Leu	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 2023	The p.R282L variant (also known as c.845G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 845. The arginine at codon 282 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Siraj AK et al. Hered Cancer Clin Pract, 2021 Dec;19:49; Subaolu A et al. Eur J Breast Health, 2023 Jan;19:55-69). However, this alteration has been detected several times in our laboratory, never in a case that meets classic Li-Fraumeni syndrome, or Chompret criteria (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have 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 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). Structurally, position R282 is located on Helix 2 (H2) of the p53 protein, is partially buried, and is involved in stabilizing Loop 1 (L1) (Tu C et al. Acta Crystallogr D Biol Chrystallogr. 2008;64(Pt 5):471-477; Ambry internal data). Another alteration at the same codon, p.R282W (c.844C>T), has been reported in multiple individuals or families with Li-Fraumeni Syndrome (LFS) or LFS-like syndrome (Toguchida J et al. N. Eng. J. Med. 1992 May;326(20):1301-8; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Kast K et al. BMC Cancer. 2012 Jun;12:217; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2021	This missense variant replaces arginine with leucine at codon 282 in the DNA binding domain 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). Arginine residue at codon 282 is known to be important for protein function, and other missense variants such as p.Arg282Trp, p.Arg282Gly and p.Arg282Pro are thought to be disease-causing (ClinVar variation ID: 12364, 140821, 376659). However, functional studies for this p.Arg282Leu variant have shown the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609) and functional in human cell growth assays (PMID: 29979965, 30224644). An external laboratory has reported detection of this variant in several individuals who do not meet classic or Chompret criteria for Li-Fraumeni syndrome (ClinVar SCV000214901.6). This variant has been reported in an individual affected with breast cancer in the literature (PMID: 28975465). This variant has not been identified 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. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Apr 12, 2021

This variant is absent from the gnomAD non-cancer v2.1.1 dataset (PM2_supporting). Transactivation assays show retained function according to Kato, et al (PMID: 12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (PMID: 30224644) (BS3). Additionally, this variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_moderate). Codon 282 is considered a hotspot (PM1) per the revised TP53 classification rules (PMID: 33300245). In summary, TP53 c.845G>T; p.Arg282Leu meets criteria to be classified as uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting; PP3_moderate; PM1; BS3. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 08, 2022

DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.845G>T, in exon 8 that results in an amino acid change, p.Arg282Leu. This sequence change has been described in one individual with breast cancer (PMID: 2897546) and has not been described in population databases such as ExAC and gnomAD. The p.Arg282Leu change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Leu substitution appears to be deleterious/possibly damaging or using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg282Leu change remains unknown at this time. -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 282 of the TP53 protein (p.Arg282Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28975465). ClinVar contains an entry for this variant (Variation ID: 182938). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function with a positive predictive value of 95%. 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. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 23, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2019

Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29979965, 14559903, 15781620, 12826609, 28301460, 28975465, 30840781) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.1

.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.5

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0, 1.0

.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.

Vest4

0.84

MutPred

0.93

Loss of MoRF binding (P = 0.1875);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.1875);.;Loss of MoRF binding (P = 0.1875);Loss of MoRF binding (P = 0.1875);Loss of MoRF binding (P = 0.1875);.;.;Loss of MoRF binding (P = 0.1875);.;.;.;

MVP

0.94

MPC

0.41

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.96

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over