17-7676154-G-C

Position:

• chr17-7676154-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000546.6(TP53):​c.215C>G​(p.Pro72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,582 control chromosomes in the GnomAD database, including 411,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.63 (31776 hom., cov: 31)
  • Exomes 𝑓: 0.72 (380188 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:25 O:1
• Conservation: PhyloP100: 1.44

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.0827485E-6).
• BP6: Variant 17-7676154-G-C is Benign according to our data. Variant chr17-7676154-G-C is described in ClinVar as [Benign]. Clinvar id is 12351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676154-G-C is described in Lovd as [Benign]. Variant chr17-7676154-G-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.215C>G	p.Pro72Arg	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.215C>G	p.Pro72Arg	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95293 AN: 151904 Hom.: 31786 Cov.: 31

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.660

GnomAD3 exomes AF: 0.668 AC: 167398 AN: 250534 Hom.: 57557 AF XY: 0.664 AC XY: 90173 AN XY: 135746

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.570

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.730

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.716 AC: 1046941 AN: 1461558 Hom.: 380188 Cov.: 80 AF XY: 0.710 AC XY: 516401 AN XY: 727064

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.714

Gnomad4 ASJ exome AF: 0.719

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.507

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.748

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.627 AC: 95285 AN: 152024 Hom.: 31776 Cov.: 31 AF XY: 0.625 AC XY: 46413 AN XY: 74294

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.700

Gnomad4 ASJ AF: 0.721

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.736

Gnomad4 NFE AF: 0.745

Gnomad4 OTH AF: 0.652

Alfa AF: 0.714 Hom.: 27610

Bravo AF: 0.617

TwinsUK AF: 0.755 AC: 2801

ALSPAC AF: 0.750 AC: 2889

ESP6500AA AF: 0.405 AC: 1784

ESP6500EA AF: 0.745 AC: 6409

ExAC AF: 0.659 AC: 79937

Asia WGS AF: 0.514 AC: 1788 AN: 3476

EpiCase AF: 0.750

EpiControl AF: 0.745

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:25 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Li-Fraumeni syndrome 1 Uncertain:1 Benign:5

Uncertain significance, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17719241, 22289634, 23729685, 22703879, 18990008, 22524816, 20128691, 12459171, 19657731, 15138483, 21323870, 18426989, 15183530, 20587514, 18256523, 19789321, 15131588, 19837266, 18567547, 23210739, 22189267, 21038427, 20019240, 23073555, 20939739, 19357867, 19521721, 20886596, 21931130, 21454683, 21814224, 22336889, 19542078, 16258005, 11983757, 19657586, 11844595, 22367371, 21245379, 9891044, 17403527, 18583979, 12567188, 19171829, 19165225, 19639206, 21124037, 23207172, 21778786, 24728327, 21283750, 22545084, 24747975, 12826609, 19470478, 8625447, 23793604, 27153395, 25896519, 15609317, 23683469, 9607760) -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Lip and oral cavity carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;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;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

CODON 72 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Acute myeloid leukemia Benign:1

Benign, no assertion criteria provided

clinical testing

Dr. Afia Zoology Lab, University of Education

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	13
DANN	Benign	0.57
DEOGEN2	Benign	0.013	T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.44	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0000081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.29	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.26	T;T;.;T;.;.;T;T;.;.;T;.;.;T;.;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.74	P;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.
Vest4		0.16
MPC		0.81
ClinPred		0.0069	T
GERP RS		1.9
Varity_R		0.086
gMVP		0.21

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: rs1042522; hg19: chr17-7579472; COSMIC: COSV52666208; COSMIC: COSV52666208;