17-7676080-C-T

Position:

• chr17-7676080-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000546.6(TP53):​c.289G>A​(p.Val97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,510 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.57

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.289G>A	p.Val97Ile	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.289G>A	p.Val97Ile	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460510 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726544

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2020

This sequence change replaces valine with isoleucine at codon 97 of the TP53 protein (p.Val97Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. 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. This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 21343334). This variant has been observed in individual(s) with breast cancer (PMID: 15564800). This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The p.V97I variant (also known as c.289G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 289. The valine at codon 97 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. This alteration has been reported in a cohort of familial breast cancer patients from India; however, this patient was also noted to carry a BRCA1 c.4956insG frameshift mutation (Hedau S et al. Breast Cancer Res Treat, 2004 Nov;88:177-86). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;D;.;.;.;.;.;.;D;.;.;T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.24	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.59
Sift	Benign	0.42	T;T;.;T;.;.;T;T;.;.;T;.;.;D;.;D
Sift4G	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;.;D;.
Polyphen		0.99	D;.;.;D;.;D;B;D;.;.;D;.;.;D;.;.
Vest4		0.13
MutPred		0.89		Loss of glycosylation at S99 (P = 0.1381);Loss of glycosylation at S99 (P = 0.1381);.;Loss of glycosylation at S99 (P = 0.1381);.;Loss of glycosylation at S99 (P = 0.1381);Loss of glycosylation at S99 (P = 0.1381);Loss of glycosylation at S99 (P = 0.1381);.;.;Loss of glycosylation at S99 (P = 0.1381);.;Loss of glycosylation at S99 (P = 0.1381);Loss of glycosylation at S99 (P = 0.1381);Loss of glycosylation at S99 (P = 0.1381);Loss of glycosylation at S99 (P = 0.1381);
MVP		0.93
MPC		1.5
ClinPred		0.87	D
GERP RS		4.6
Varity_R		0.49
gMVP		0.22

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: rs730882023; hg19: chr17-7579398; COSMIC: COSV53077329; COSMIC: COSV53077329;