chr17-7676041-G-T

Position:

• chr17-7676041-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• 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 Likely_pathogenic. Variant got 6 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].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.328C>A	p.Arg110Ser	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.328C>A	p.Arg110Ser	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2021	The 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 submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 03, 2020	This 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 submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

This 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 submitter

clinical testing

GeneDx

Sep 26, 2023

Not 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
MutationAssessor	Benign	1.6	.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.
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

Other links and lift over

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