rs587781371

chr17-7676041-G-Achr17-7676041-G-Cchr17-7676041-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:11
• Conservation: PhyloP100: 0.507

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 Uncertain_significance. Variant got 0 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
• 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.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.328C>T	p.Arg110Cys	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.328C>T	p.Arg110Cys	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

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: 5 AN: 251288 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135844

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: 21 AN: 1460108 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726334

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: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

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.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain: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. -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

not specified Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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	Invitae	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

Mar 04, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant has been reported as a somatic finding in various tumor tissues and published functional studies indicate that the variant results in decreased apoptotic activity (Kharaziha et al., 2019); This variant is associated with the following publications: (PMID: 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 29979965, 31081129, 30224644, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609) -

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 “With Uncertain significance allele”, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
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	N
LIST_S2	Uncertain	0.93	D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.39	T
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	D
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

Other links and lift over

dbSNP: rs587781371; hg19: chr17-7579359; COSMIC: COSV52684761; COSMIC: COSV52684761;