17-7676155-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2BP4

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.214C>G variant in TP53 is a missense variant predicted to cause substitution of proline by alanine at amino acid 72 (p.Pro72Ala).This is a polymorphic residue (alternate nomenclature: p.Arg72). This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.215412; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.2; 2/6/2025) 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
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:11B:1

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 Likely_benign. Variant got -5 ACMG points.

BP4

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.214C>G	p.Pro72Ala	missense_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.214C>G	p.Pro72Ala	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4		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: Likely benign

Submissions summary: Uncertain:11Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. 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. -

Feb 06, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.214C>G variant in TP53 is a missense variant predicted to cause substitution of proline by alanine at amino acid 72 (p.Pro72Ala). This is a polymorphic residue (alternate nomenclature: p.Arg72). This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.215412; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.2; 2/6/2025) -

Li-Fraumeni syndrome 1

Uncertain:2

Nov 24, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 02, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 07, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Choroid plexus papilloma;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931038:Familial pancreatic carcinoma;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5

Uncertain:1

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial pancreatic carcinoma

Uncertain:1

Jul 08, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP53-related disorder

Uncertain:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.;.;.;.

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