rs587781371

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

The NM_000546.6(TP53):c.328C>T(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11O:1

Conservation

PhyloP100: 0.507

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 0 ACMG points.

PM1

In a region_of_interest Required for interaction with ZNF385A (size 200) in uniprot entity P53_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000546.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7676040-C-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.328C>T	p.Arg110Cys	missense_variant	4/11	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.328C>T	p.Arg110Cys	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251288

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460108

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726334

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:

0.000150

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 05, 2023	The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by cysteine, an amino acid with highly dissimilar properties. In one Japanese case-control study, this variant was not identified in 7051 breast cancer cases and was seen in 1/11241 controls (Momozowa Y et al. Nat Commun 2018 10;9(1):4083). This alteration has also been reported in a high-risk breast cancer proband from Sweden (Kharaziha P et al. Clin Genet 2019 09;96(3):216-225). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni syndrome (LFS) based on personal and family history (Rines RD et al. Carcinogenesis. 1998 Jun;19(6):979-84; Masciari S et al. Genet Med. 2011 Jul;13(7):651-7). This alteration has been observed in individuals with TP53 related tumors, but not classic Li-Fraumeni syndrome (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Apr 27, 2023	This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. 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 pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

not specified

Uncertain:2

Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2023	Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes. c.328C>T has been reported in the literature in individuals affected with various cancers without evidence of causality (e.g. Kharaziha_2019, Kobayashi_2018, LernerEllis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Kharaziha_2019). The following publications have been ascertained in the context of this evaluation (PMID: 9290701, 31081129, 30613367, 32885271). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. 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 06, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein (p.Arg110Cys). This variant is present in population databases (rs587781371, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 31081129, 32885271; Invitae). ClinVar contains an entry for this variant (Variation ID: 142206). Advanced modeling performed at Invitae incorporating data from internal and/or published 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9290701, 12826609, 29979965, 30224644, 31081129). 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. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 13, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 2024

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 34605602, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 31081129, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609, 11782540, 25952993, 23246812, 22186996, 21519010, 21343334, 20407015, 17606709, 27276561, 29979965, 37352403, 30224644, 36353970, 32885271, 15510160, 30327374, 30613367, 27463065, 27895058, 27959731, 27680515, 26230955) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant (see examples: Holstege 2009, Pain 2017, Holstege 2010). The variant was also identified in dbSNP (ID: rs587781371) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, in ClinVar (classified as a variant of uncertain significance 4x by Ambry Genetics, Color Genomics, Invitae, and GeneDx), Cosmic (17x somatic entries), and IARC TP53 Database (13 somatic mutations). The variant was not identified in COGR, LOVD 3.0, or the Database of germline p53 mutations. The variant was identified in control databases in 5 of 246096 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the Finnish population in 5 of 22298 chromosomes (freq: 0.000224), but not in the African, Ashkenazi Jewish, East Asian, European (Non-Finnish), Latino, or South Asian populations. The p.Arg110 residue has been classified as a somatic mutational hotspot (Walker et al 1999). Variants at the same amino acid residue have been previously seen and are classified on ClinVar: p.Arg110Pro is classified as likely pathogenic; p.Arg110Leu is classified as likely pathogenic and as a variant of uncertain significance; and p.Arg110Ser and p.Arg110His are both classified as variants of uncertain significance. The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.65

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

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.52

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.

MutationTaster

Benign

0.99

N;N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.4

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

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

D;.;.;B;.;B;D;B;.;.;B;.;.;B;.;.

Vest4

0.53

MutPred

0.71

Gain of catalytic residue at L111 (P = 0.0334);Gain of catalytic residue at L111 (P = 0.0334);.;Gain of catalytic residue at L111 (P = 0.0334);.;Gain of catalytic residue at L111 (P = 0.0334);Gain of catalytic residue at L111 (P = 0.0334);Gain of catalytic residue at L111 (P = 0.0334);.;.;Gain of catalytic residue at L111 (P = 0.0334);.;Gain of catalytic residue at L111 (P = 0.0334);Gain of catalytic residue at L111 (P = 0.0334);Gain of catalytic residue at L111 (P = 0.0334);Gain of catalytic residue at L111 (P = 0.0334);

MVP

0.97

MPC

1.9

ClinPred

0.76

GERP RS

0.048

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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