17-7676155-G-C

Position:

chr17-7676155-G-C

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: This is a polymorphic residue (alternate nomenclature: p.Arg72). BP4 (missense variants): This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). In summary, the clinical significance of TP53 c.214C>G (p.Pro72Ala) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000070/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:10

Conservation

PhyloP100: -0.364

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.214C>G	p.Pro72Ala	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 linkuse as main transcript	c.214C>G	p.Pro72Ala	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250672

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	This missense variant replaces proline with alanine at codon 72 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have reported for this variant as functional in yeast based transcriptional transactivation studies (PMID: 12826609). This variant has been reported in individuals affected with breast cancer (PMID: 30287823, 33471991) as well as unaffected controls (PMID: 30287823, 32980694, 33471991). This variant has also been reported in the normal tissue of an individual affected with lung and colon cancer (PMID: 31472337). This variant has been identified in 4/282046 chromosomes 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, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Apr 12, 2021	This is a polymorphic residue (alternate nomenclature: p.Arg72). BP4 (missense variants): This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). In summary, the clinical significance of TP53 c.214C>G (p.Pro72Ala) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 72 of the TP53 protein (p.Pro72Ala). This variant is present in population databases (rs587782769, gnomAD 0.02%). 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: 142854). 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 23713777). 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. -

Li-Fraumeni syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 24, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 11, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2016	This variant is denoted TP53 c.214C>G at the cDNA level, p.Pro72Ala (P72A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant was observed in the tissue of a hepatocellular carcinoma and a high-grade glioblastoma as a somatic variant (Derakhshandeh-Peykar 2011, Ji 2014). TP53 Pro72Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Pro72Ala occurs at a position that is not conserved, with Alanine being the naturally occurring amino acid at this position in a few mammals, and is located in the SH3 domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Pro72Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2022	The frequency of this variant in the general population, 0.0002 (4/19940 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported with other variants in various tumors without specifying its germline status including sebaceous carcinoma (PMID: 27311873 (2016)), non small cell lung cancer (PMIDs: 28780976 (2018), 29575851 (2018)), invasive mucinous adenocarcinoma of the lung (PMID: 31472337 (2019)), soft tissue carcinoma (PMID: 31089155 (2019)), oral neoplasm (PMID: 31845386 (2020)), rhabdomyosarcoma (PMID: 34166060 (2021)), and was also identified in a patient affected with Peutz-Jeghers syndrome (PMID: 34754157 (2021)). Functional studies investigating the effect of this variant upon transactivation activity and the capacity to induce apoptosis are inconclusive (PMIDs: 12826609 (2003), 23713777 (2014), The TP53 Database (https://tp53.isb-cgc.org/)), further research is needed. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This missense variant replaces proline with alanine at codon 72 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). IARC transactivation assays reported the variant protein to be functional (PMID: 12826609). This variant has been reported in individuals affected with breast cancer (PMID: 30287823, 33471991) as well as unaffected controls (PMID: 30287823, 32980694, 33471991). This variant has also been reported in the normal tissue of an individual affected with lung and colon cancer (PMID: 31472337). This variant has been identified in 4/282046 chromosomes 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	Ambry Genetics	Nov 30, 2022	The p.P72A variant (also known as c.214C>G), located in coding exon 3 of the TP53 gene, results from a C to G substitution at nucleotide position 214. The proline at codon 72 is replaced by alanine, an amino acid with highly similar properties. This variant is reported to have transactivation similar to wild type in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.P72A remains unclear. -

TP53-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

The TP53 c.214C>G variant is predicted to result in the amino acid substitution p.Pro72Ala. This variant has been reported in individuals with breast cancer as well as in controls (Supplementary Data 1 and 2, Momozawa et al. 2018. PubMed ID: 30287823; Supplementary Data, Dorling et al. 2021. PubMed ID: 33471991; Supplementary Table 2, Okawa et al. 2022. PubMed ID: 36243179). It was detected in both tumor and normal tissue in an individual with invasive mucinous adenocarcinoma (Kawai et al. 2019. PubMed ID: 31472337). This variant has also been detected in an individual with Peutz-Jeghers syndrome, who also carried an SLX4 variant (Gu et al. 2021. PubMed ID: 34754157). Functional studies have shown this variant does not have a significant negative impact on protein function (Ji et al. 2014. PubMed ID: 23713777; Kato et al. 2003. PubMed ID: 12826609). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as a variant of uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142854/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.22

CADD

Benign

0.33

DANN

Benign

0.29

DEOGEN2

Benign

0.0068

T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.56

T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.067

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

0.46

.;.;.;N;.;N;N;N;.;.;N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.13

N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.48

T;T;.;T;.;.;T;T;.;.;T;.;.;T;.;T

Sift4G

Benign

0.93

T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.

Polyphen

0.0030

B;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.

Vest4

0.16

MutPred

0.17

Loss of catalytic residue at P71 (P = 0.0255);Loss of catalytic residue at P71 (P = 0.0255);.;Loss of catalytic residue at P71 (P = 0.0255);.;Loss of catalytic residue at P71 (P = 0.0255);Loss of catalytic residue at P71 (P = 0.0255);Loss of catalytic residue at P71 (P = 0.0255);.;.;Loss of catalytic residue at P71 (P = 0.0255);.;Loss of catalytic residue at P71 (P = 0.0255);Loss of catalytic residue at P71 (P = 0.0255);Loss of catalytic residue at P71 (P = 0.0255);Loss of catalytic residue at P71 (P = 0.0255);

MVP

0.72

MPC

0.62

ClinPred

0.0066

GERP RS

0.24

Varity_R

0.072

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over