17-7676056-C-T

Position:

• chr17-7676056-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.313G>A​(p.Gly105Ser) variant causes a missense change. 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. G105C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.36

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 18 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-7676056-C-T is Pathogenic according to our data. Variant chr17-7676056-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428884.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.313G>A	p.Gly105Ser	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.313G>A	p.Gly105Ser	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2016	<span style="font-size:12px">The p.G105S variant (also known as c.313G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 313. The glycine at codon 105 is replaced by serine, an amino acid with similar properties.<span style="font-family:arial,sans-serif">This alteration is located in the functionally critical DNA binding domain and has shown a loss of transactivation activity in yeast based functional studies (Kato S et al. <span style="font-family:arial,sans-serif">Proc<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Natl<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Acad<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Sci USA<span style="font-family:arial,sans-serif">. 2003 Jul 8;100(14):8424-9). Although this specific alteration has not been reported in the literature, another alteration at this position (p.G105C) was reported in a family with classic Li-Fraumeni Syndrome, where the proband had three primary breast cancers by the age of 31, and a family history of early onset breast cancer and brain tumors (Bendig I et al., <span style="font-family:arial,sans-serif">Cancer Genet. <span style="font-family:arial,sans-serif">Cytogenet<span style="font-family:arial,sans-serif">.<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">2004 Oct; 154(1):22-6). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., <span style="font-family:arial,sans-serif">Science 1994 Jul; 265(5170):346-55). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT <span style="font-family:arial,sans-serif">in silico<span style="font-family:arial,sans-serif"> analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:1

Likely 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 15, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly105 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644, 30840781). 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. ClinVar contains an entry for this variant (Variation ID: 428884). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae; external communications). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the TP53 protein (p.Gly105Ser). -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;D;.;.;.;.;.;.;D;.;.;D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0070	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.
Polyphen		1.0	D;.;.;P;.;D;D;D;.;.;P;.;.;P;.;.
Vest4		0.84
MutPred		0.94		Gain of disorder (P = 0.0607);Gain of disorder (P = 0.0607);.;Gain of disorder (P = 0.0607);.;Gain of disorder (P = 0.0607);Gain of disorder (P = 0.0607);Gain of disorder (P = 0.0607);.;.;Gain of disorder (P = 0.0607);.;Gain of disorder (P = 0.0607);Gain of disorder (P = 0.0607);Gain of disorder (P = 0.0607);Gain of disorder (P = 0.0607);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1060501195; hg19: chr17-7579374; COSMIC: COSV53015551; COSMIC: COSV53015551;