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17-7676041-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000546.6(TP53):c.328C>A(p.Arg110Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)

Consequence

TP53
NM_000546.6 missense

Scores

2
7
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7676040-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.328C>A p.Arg110Ser missense_variant 4/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.328C>A p.Arg110Ser missense_variant 4/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 06, 2021The p.R110S variant (also known as c.328C>A) is located in coding exon 3 of the TP53 gene. This alteration results from a C to A substitution at nucleotide position 328. The arginine at codon 110 is replaced by serine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration is proficient 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). Other alterations at this codon (p.R110L, p.R110P) have been reported in patients satisfying clinical criteria for Li-Fraumeni syndrome (Alsner et al. Clin Cancer Res. 2000. 6:3923-3931; Masciari et al. Genet Med. 2011.13(7):651-7; Rath MG et al. Breast Cancer Res. Treat. 2013 May;139(1):193-8; Rines RD et al. Carcinogenesis 1998 Jun;19(6):979-84). 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 limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 03, 2020This missense variant replaces arginine with serine at codon 110 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported conflicting findings for this variant, for which this variant was nonfunctional in yeast transactivation assays (PMID: 12826609 and IARC database) and functional in human cell growth suppression assays and cell proliferation assay (PMID: 29979965, 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. Different variants affecting the same position (p.Arg110Pro and p.Arg110Leu) are considered to be disease-causing (ClinVar variation ID: 233627, 406597, 641505), suggesting that arginine at this position is important for protein structure and function. 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, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 09, 2023This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 110 of the TP53 protein (p.Arg110Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 140921). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). This variant disrupts the DNA binding domain which is critical for DNA binding activity (PMID: 26205489). While functional studies have not been performed to directly test the effect of this variant on TP53 protein function, this suggests that disruption of this region of the protein is causative of disease. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 26, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: non-functional transactivation but no impact on growth suppression ability (Kato et al., 2003; Kotler et al., 2018; Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 14559903, 15510160, 30224644, 29979965, 12826609) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
Cadd
Benign
20
Dann
Uncertain
0.99
DEOGEN2
Benign
0.41
T;T;.;D;.;.;.;.;.;.;D;.;.;D;D;.
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.086
N
LIST_S2
Uncertain
0.91
D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.44
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.80
N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;D
REVEL
Uncertain
0.53
Sift
Uncertain
0.018
D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G
Benign
0.085
T;T;T;T;T;T;T;T;T;T;T;T;T;.;D;.
Polyphen
0.78
P;.;.;P;.;P;B;P;.;.;P;.;.;P;.;.
Vest4
0.25
MutPred
0.53
Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);.;Gain of disorder (P = 0.0363);.;Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);.;.;Gain of disorder (P = 0.0363);.;Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);Gain of disorder (P = 0.0363);
MVP
0.94
MPC
1.7
ClinPred
0.63
D
GERP RS
0.048
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.44
gMVP
0.30

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.

Other links and lift over

dbSNP: rs587781371; hg19: chr17-7579359; COSMIC: COSV53551526; COSMIC: COSV53551526; API