rs11540654

chr17-7676040-C-Achr17-7676040-C-Gchr17-7676040-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000546.6(TP53):c.329G>T(p.Arg110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.604

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 Pathogenic. Variant got 16 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-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 17-7676040-C-A is Pathogenic according to our data. 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. Variant chr17-7676040-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.329G>T	p.Arg110Leu	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.329G>T	p.Arg110Leu	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460086 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726322

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

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: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 14, 2021	This missense variant replaces arginine with leucine at codon 110 in the DNA binding domain 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 have shown the mutant protein to be defective in DNA binding and transactivation activity (PMID 9290701, 12826609, 17724467, 24076587) and non-functional in cell growth assay (PMID: 29979965). This variant has been reported in multiple individuals affected with affected with Li-Fraumeni syndrome (PMID: 9667734, 18511570; ClinVar SCV000545344.5). This variant has been observed to de de novo in an individual affected with Li-Fraumeni syndrome-associated cancers (ClinVar SCV000545344.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position, p.Arg110Pro, is known to be disease-causing (ClinVar variation ID: 233627), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2015	The p.R110L variant (also known as c.329G>T), located in coding exon 3 of the TP53 gene, results from a G to T substitution at nucleotide position 329. The arginine at codon 110 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in one study as a known germline mutation from a cohort of Li-Fraumeni patient samples used for analysis of technique of two-dimentional gene scanning (Rines RD et al. Carcinogenesis 1998 Jun;19(6):979-84). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity but no dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). In addition, two other alterations (p.R110H and p.R110P) have been reported at this position in patients with breast cancer and/or family history meeting classic Li-Fraumeni syndrome criteria (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). This variant was previously reported in the SNPDatabase as rs11540654. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 200000 alleles tested) in our clinical cohort, and has been found in individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2019	The p.Arg110Leu variant in TP53 has been reported in 2 individuals with features of Li-Fraumeni syndrome (Rines 1998, Bougeard 2008). This variant has also been reported in ClinVar (Variation ID 406597) and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Another variant involving this codon (p.Arg110Pro) has been identified in individuals with Li-Fraumeni syndrome (Variation ID 233627). In vitro functional studies support an impact on protein function (Mizuarai 2006, Grochova 2008, Xu 2011). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PM5, PS3_Supporting, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 110 of the TP53 protein (p.Arg110Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 9667734, 18511570; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 406597). 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 have shown that this missense change affects TP53 function (PMID: 9290701, 16778209, 17724467, 21445056, 24076587). This variant disrupts the p.Arg110 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 21552135, 23894400, 23897043, 24076587). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 12, 2024	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20505364, 24076587, 29979965]. -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

-

- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D;.;D;.;.;.;.;.;.;D;.;.;D;D;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.97	D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.9	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.011	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G	Uncertain	0.037	D;D;T;D;T;D;D;D;T;T;D;T;D;.;D;.
Polyphen		0.78	P;.;.;B;.;P;B;P;.;.;B;.;.;P;.;.
Vest4		0.72
MutPred		0.84		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.98
MPC		1.7
ClinPred		0.97	D
GERP RS		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.37

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: rs11540654; hg19: chr17-7579358; COSMIC: COSV52662399; COSMIC: COSV52662399;