17-7674220-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PM2_SupportingPS3PS2PS4PM1PP3PP1_ModeratePP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID:9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID:1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID:8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000387/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:47O:2

Conservation

PhyloP100: 6.16

Publications

1922 publications found

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 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Li-Fraumeni syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
Li-Fraumeni syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
adrenocortical carcinoma, hereditary
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
bone marrow failure syndrome 5
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
colorectal cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
choroid plexus carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS2

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

PS3

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

PS4

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

PM1

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

PM2

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

PP1

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

PP3

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

PP4

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.743G>A	p.Arg248Gln	missense_variant	Exon 7 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.743G>A	p.Arg248Gln	missense_variant	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251474

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727134

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111776

Other (OTH)

AF:

0.0000166

AC:

AN:

60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000903677), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151938

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41354

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000336

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:47Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

May 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). 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 damaging. Based on the available information, this variant is classified as pathogenic.

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 02, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting

Dec 03, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644)

Jun 09, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 25, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Li-Fraumeni syndrome 1

Pathogenic:8

Feb 23, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Apr 12, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056].

Feb 17, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 15, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 27, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jul 24, 2014

Pathway Genomics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 27, 2012

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma).

Hereditary cancer-predisposing syndrome

Pathogenic:7

Aug 26, 2022

BRCAlab, Lund University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 03, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation.

May 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function Functional studies have shown the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

May 22, 2023

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.743G>A, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Arginine by Glutamine at codon 248, p.(Arg248Gln). It is located in a mutational hotspot (PM1). This variant is found in 2/236936 alleles at a frequency of 0.0008% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C35; BayesDel: 0.47 (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 9 families/individuals with a TP53-related phenotype, which awards 5.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 7887414, 19556618, 25612911, 28573494, 28154273, 8118819, among others) (PS4). It has been reported in ClinVar, LOVD and CancerHotspots. Based on the currently available information, c.743G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.

Jan 01, 2020

GeneKor MSA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356).

Li-Fraumeni syndrome

Pathogenic:5

Sep 20, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Aug 05, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)

Nov 23, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic.

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 17606709, 20128691, 21343334). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8062826, 9546439, 12826609, 15722483; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Jul 02, 2018

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial cancer of breast

Pathogenic:2

Mar 19, 2021

University Health Network, Princess Margaret Cancer Centre

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:case-control

Adrenocortical carcinoma, hereditary

Pathogenic:2

Jul 20, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Adrenal cortex carcinoma

Pathogenic:1

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Malignant tumor of urinary bladder

Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Rhabdomyosarcoma

Pathogenic:1

Sep 01, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Apr 22, 2024

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Breast carcinoma

Pathogenic:1

Aug 08, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Lip and oral cavity carcinoma

Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Ductal carcinoma in situ

Pathogenic:1

Mar 19, 2021

University Health Network, Princess Margaret Cancer Centre

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Multiple myeloma

Pathogenic:1

Aug 31, 2019

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Lymphoma

Pathogenic:1

Jul 25, 2019

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

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

Pathogenic:1

Dec 28, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TP53-related disorder

Pathogenic:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TP53 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with Li-Fraumeni syndrome and various cancers including breast cancer and osteosarcoma (see for example: Stjepanovic. 2018. PubMed ID: 30092803; Wu. 2011. PubMed ID: 21305319; Monti. 2007. PubMed ID: 17606709; Toguchida. 1992. PubMed ID: 1565143; Guindalini. 2022. PubMed ID: 35264596). In vitro experiments have shown the c.743G>A variant results in a dominant-negative allele, and reduces p53 protein activity by ~75% compared to wild-type (Monti. 2011. PubMed ID: 21343334; Zerdoumi. 2017. PubMed ID: 28369373). This variant is reported to segregate with disease within families (Monti. 2007. PubMed ID: 17606709; Wu. 2011. PubMed ID: 21305319), and has been reported to arise as a de novo mosaic germline variant that was later found to be homozygous in numerous tumor samples (Behjati. 2014. PubMed ID: 24810334). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 Variant Curation Expert Panel (VCEP; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed), and is classified as pathogenic and likely pathogenic by many other labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12356/). We interpret this variant as pathogenic.

Sarcoma

Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Colorectal cancer

Other:1

Apr 12, 2016

Genome Sciences Centre, British Columbia Cancer Agency

Significance:

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.

PhyloP100

6.2

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.8

D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0050

D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;D;D;D;D;.

Vest4

0.95

ClinPred

0.98

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.87

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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