17-7676558-G-C

Position:

• chr17-7676558-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000546.6(TP53):​c.37C>G​(p.Pro13Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.86

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-7676558-G-C is Benign according to our data. Variant chr17-7676558-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1735038.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.37C>G	p.Pro13Ala	missense_variant	2/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.37C>G	p.Pro13Ala	missense_variant	2/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 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	May 30, 2024	This missense variant replaces proline with alanine at codon 13 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Experimental studies have reported this variant as functional in a yeast based transcriptional transactivation study and human cell growth suppression assay (PMID: 12826609, 30224644) . This variant has been reported in individuals affected with breast cancer (PMID: 33606809). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 13 of the TP53 protein (p.Pro13Ala). 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: 1735038). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	2.0	.;.;M;M;M;M;M;.;.;.;.;.
PROVEAN	Uncertain	-3.1	D;D;D;.;D;D;D;.;N;D;.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;.;D;D;.;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;.;.;D;.
Polyphen		1.0	D;.;D;D;D;D;D;.;P;D;.;.
Vest4		0.55
MutPred		0.55		Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);Loss of glycosylation at P13 (P = 0.0233);
MVP		0.94
MPC		1.6
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7579876;