rs375444154

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3PM2_SupportingBS3BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.1003C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 335 (p.Arg335Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; ClinVar SCV: SCV000629764.4). This variant has an allele frequency of 0.000001859 (3/1613806 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.275; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, PP3. (Bayesian Points: -3; VCEP specifications version 2.2; 2/6/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000009/MONDO:0018875/009

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8

Conservation

PhyloP100: 3.19

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 Likely_benign. Variant got -3 ACMG points.

PM2

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

PP3

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

BS2

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 link	c.1003C>T	p.Arg335Cys	missense_variant	10/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.1003C>T	p.Arg335Cys	missense_variant	10/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461594

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727084

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:3

Uncertain significance, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 04, 2020	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show retained 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). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor (SCV000629764.4). In summary, the clinical significance of TP53 c.1003C>T(p.Arg335Cys) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS3, PP3, BS2_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces arginine with cysteine at codon 335 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). Experimental functional studies of this variant have indicated that the transactivation activity (PMID: 12826609) and oligomerization of the protein (PMID 16007150) are not impaired. The variant also display no dominant-negative behavior or loss-of-function in human cell growth suppression assays (PMID: 30224644). However another study showed partial effects on transactivation activity, repression activity, DNA binding, and induction of apoptosis (PMID: 10653977). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 335 of the TP53 protein (p.Arg335Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 35047863). ClinVar contains an entry for this variant (Variation ID: 141159). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2023	This missense variant replaces arginine with cysteine at codon 335 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). Experimental functional studies of this variant have indicated that the transactivation activity (PMID: 12826609) and oligomerization of the protein (PMID 16007150) are not impaired. The variant also display no dominant-negative behavior or loss-of-function in human cell growth suppression assays (PMID: 30224644). However another study showed partial effects on transactivation activity, repression activity, DNA binding, and induction of apoptosis (PMID: 10653977). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2023	The p.R335C variant (also known as c.1003C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1003. The arginine at codon 335 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant is in the tetramerization domain of the TP53 protein and is reported to have transactivation similar to wild type in yeast based assays, and maintain the ability to form tetrames (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Kawaguchi T et al. Oncogene. 2005 Oct 20;24(46):6976-81). However, another study indicated that this alteration showed a decrease from wild type in DNA binding, transactivation activity, apoptosis induction and binding to the PAb421 regulatory protein, but did not affect TP53 gene repressor activity or oligomerization (Atz J et al. J. Cell. Biochem., 2000 Jan;76:572-84). Additional studies conducted in human cell lines indicate this alteration has no dominant negative effect and remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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 limited at this time, the clinical significance of this alteration remains unclear. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 14, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: functional transactivation activity, normal temperature sensitivity, no impact on growth suppression, decreased DNA binding, decreased apoptosis, and decreased gene repressor activity (Atz 2000, Kato 2003, Shiraishi 2004, Giacomelli 2018); This variant is associated with the following publications: (PMID: 14559903, 30224644, 16007150, 19011621, 10653977, 23515929, 24665023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.95

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

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

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.8

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

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.69

MVP

0.98

MPC

0.43

ClinPred

0.99

GERP RS

3.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.3

Varity_R

0.92

gMVP

0.69

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