17-7676040-C-G

Position:

• chr17-7676040-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000546.6(TP53):​c.329G>C​(p.Arg110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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]

TP53 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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
• 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 Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant 17-7676040-C-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.329G>C	p.Arg110Pro	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	c.329G>C	p.Arg110Pro	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

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 13, 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: 24076587, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21552135, 23894400, 29070607]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 17, 2023	The p.R110P pathogenic mutation (also known as c.329G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 329. The arginine at codon 110 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in two male individuals from separate families with Li-Fraumeni syndrome, one with gastric cancer at 32 years of age, and the other with two primary sarcomas at 37 and 44 years of age (Mitchell G et al. PLoS ONE. 2013; 8(7):e69026; Masciari S et al. Genet. Med. 2011 Jul; 13(7):651-7). This variant has also been reported and confirmed de novo in an individual with 2 soft tissue sarcomas, diagnosed at age 38 years and 44 years (Renaux-Petel M et al. J. Med. Genet. 2018 Mar;55(3):173-180). Multiple functional studies have demonstrated that this alteration is deficient in transcriptional activation, DNA binding, and induction of apoptosis (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32). Studies conducted in human cell lines indicate this alteration is deficient 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). In addition, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 110 of the TP53 protein (p.Arg110Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with classical Li-Fraumeni syndrome (LFS) (PMID: 21552135, 23894400, 29070607; Invitae). ClinVar contains an entry for this variant (Variation ID: 233627). 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, 23897043, 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: 16778209, 21445056, 24076587; Invitae). 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. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 25, 2023

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Aug 14, 2024

Combined evidence strength is Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars (PP5). Hot-spot of length 17 amino-acids has 79 missense/in-frame variants (26 pathogenic variants, 52 uncertain variants and 1 benign variant), which qualifies as strong pathogenic.UniProt protein P53_HUMAN has 1149 missense/in-frame variants (386 pathogenic variants, 757 uncertain variants and 6 benign variants), which qualifies as moderate pathogenic.UniProt protein P53_HUMAN region of interest 'Required for interaction with ZNF385A, CCAR2, HIPK1, WWOX' which qualifies as moderate and supporting pathogenic (PM1). Alternative variant chr17:7676041G>A (Arg110Cys), (Arg110Leu) are classified likely pathogenic and pathogenic by the varsome community using the germline classifier (PM5). Variant not found in gnomAD genomes.Variant not found in gnomAD exomes (PM2). MetaRNN = 0.777= supporting pathogeni (PP3). We identified this heterozygous variant in a 51 year old woman with triple-negative breast cancer and a family history of brain cancer and breast cancer. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;.;D;.;.;.;.;.;.;D;.;.;D;D;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.96	D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.014	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G	Uncertain	0.035	D;D;T;D;T;D;D;D;T;T;D;T;D;.;D;.
Polyphen		0.98	D;.;.;P;.;P;D;P;.;.;P;.;.;D;.;.
Vest4		0.63
MutPred		0.65		Loss of catalytic residue at R110 (P = 0.0149);Loss of catalytic residue at R110 (P = 0.0149);.;Loss of catalytic residue at R110 (P = 0.0149);.;Loss of catalytic residue at R110 (P = 0.0149);Loss of catalytic residue at R110 (P = 0.0149);Loss of catalytic residue at R110 (P = 0.0149);.;.;Loss of catalytic residue at R110 (P = 0.0149);.;Loss of catalytic residue at R110 (P = 0.0149);Loss of catalytic residue at R110 (P = 0.0149);Loss of catalytic residue at R110 (P = 0.0149);Loss of catalytic residue at R110 (P = 0.0149);
MVP		0.99
MPC		2.0
ClinPred		0.90	D
GERP RS		-0.96
Varity_R		0.98
gMVP		0.80

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

Other links and lift over

dbSNP: rs11540654; hg19: chr17-7579358; COSMIC: COSV52668419; COSMIC: COSV52668419;