rs772773208

chr17-7673582-G-Achr17-7673582-G-Cchr17-7673582-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000546.6(TP53):c.946C>T(p.Pro316Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P316T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.43

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 509 pathogenic changes around while only 116 benign (81%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2494623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.946C>T	p.Pro316Ser	missense_variant	9/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.946C>T	p.Pro316Ser	missense_variant	9/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 316 of the TP53 protein (p.Pro316Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 823268). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 01, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0080	T;.;.;.;.;T;T;.;T;.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.023
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL	Uncertain	0.44
Sift	Benign	0.059	T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;D
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.021, 0.036, 1.0	.;.;.;.;.;.;.;.;B;.;B;D;B;.;.;B;.;.;.
Vest4		0.32
MutPred		0.25		Gain of phosphorylation at P316 (P = 0.0178);.;.;.;.;.;.;.;Gain of phosphorylation at P316 (P = 0.0178);.;Gain of phosphorylation at P316 (P = 0.0178);Gain of phosphorylation at P316 (P = 0.0178);Gain of phosphorylation at P316 (P = 0.0178);.;.;Gain of phosphorylation at P316 (P = 0.0178);.;.;.;
MVP		0.92
MPC		0.077
ClinPred		0.28	T
GERP RS		3.0
Varity_R		0.098
gMVP		0.50

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: rs772773208; hg19: chr17-7576900;