17-7675070-C-T

Position:

chr17-7675070-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_000546.6(TP53):c.542G>A(p.Arg181His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: 0.789

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:

TP53 (HGNC:):

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PP5

Variant 17-7675070-C-T is Pathogenic according to our data. Variant chr17-7675070-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.542G>A	p.Arg181His	missense_variant	5/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.542G>A	p.Arg181His	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

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:

0.00

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251324

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135850

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 SAS 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:

0.0000150

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000180

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2024	Observed in individuals with early-onset breast and other Li-Fraumeni-related cancers, including one patient with pediatric-onset rhabdomyosarcoma, but does not appear to consistently result in classic Li-Fraumeni syndrome (PMID: 1591732, 21059199, 23175693, 24556621, 25186627, 29077256, 28767289, 30067863, 30264118, 29300620, 30653764, 34863587, 35512711, 29847298); Published functional studies demonstrate defective binding and transactivation of apoptotic target genes with a consequent impact on apoptotic activity, and mixed results regarding transactivation of other p53 response elements and growth suppression (PMID: 8675009, 9546439, 11429705, 12826609, 17606709, 20128691, 20471942, 21343334, 27873457, 29979965, 30224644, 35043155, 34907344); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21059199, 11793474, 24729566, 27586204, 17311302, 7981076, 8308926, 31543368, 30840781, 35043155, 36353970, 1591732, 20128691, 9546439, 17606709, 21343334, 20471942, 27101868, 26650777, 26484312, 25625332, 15580553, 24449472, 14559903, 1631137, 26762747, 27873457, 11429705, 25186627, 29979965, 28724667, 28767289, 29522266, 23175693, 28861920, 15221755, 18818522, 28772290, 26000489, 30067863, 30653764, 30264118, 24556621, 29300620, 29077256, 31056747, 31115261, 8675009, 1581912, 31026031, 30720243, 31119730, 15925506, 30352134, 30224644, 31105275, 31447099, 32676327, 32923878, 33818021, 33880204, 33194542, 33245408, 31948886, 32029870, 33230179, 35512711, 34863587, 36628428, 36262946, 35820297, 35626031, 34308104, 35875466, 34282142, 33858029, 32817165, 34240179, 8102535, 24797764, 34725851, 28445466, 35802772, 37007070, 36831331, 36260514, 36933394, 34907344, 35659507, 34793666, 32998877, 12826609, 15510160, 34273903, 22768918, 29847298, 34326862) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 15, 2023	The TP53 c.542G>A (p.Arg181His) variant has been reported in the published literature in individuals and families with cancer diagnoses consistent with Li-Fraumeni syndrome (PMID: 1591732 (1992), 1631137 (1992), 18689542 (2008), 21059199 (2010), 23175693 (2013), 28724667 (2017), 33818021 (2021), 35875466 (2022)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 11429705 (2001), 11896595 (2002), 20128691 (2010), 20471942 (2010), 21343334 (2011)). The frequency of this variant in the general population, 0.000031 (4/129056 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2019	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.542G>A, in exon 5 that results in an amino acid change, p.Arg181His. This sequence change has been described in the gnomAD database with a low population frequency of 0.0014% (dbSNP rs397514495). The p.Arg181His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg181His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has been previously reported in multiple individuals with TP53-related cancers such as breast cancer, adrenocortical carcinoma, and pancreatic cancer (PMIDs: 1591732, 1631137, 21059199, 30653764). Functional studies have demonstrated that the p.Arg181His change may impact protein function (PMIDs: 15580553, 21343334, 20128691). Furthermore, other nucleotide changes affecting the Arg181 residue have also been reported in individuals with TP53-related cancers suggesting that this residue is functionally and clinically important (PMIDs:1581912, 8308926, 15925506). -

Hereditary cancer-predisposing syndrome

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	Jan 18, 2023	c.542G>A, located in exon 5 of the TP53 gene, is predicted to result in the substitution of Arginine by Histidine at codon 181, p.(Arg181His). This variant is found in 4/268208 alleles at a frequency of 0.0014% 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: C25; BayesDel: 0.26) (PP3). Transactivation assays show a partially functional allele according to Kato 2003 (PMID: 12826609) and there is a second assay showing low function (PMID: 9546439) (PS3_moderate). At least, this variant has been reported in 7 individuals affected with a TP53-related phenotype, which awards 4 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 1631137, 23175693, 21059199) (PS4). It has been reported in ClinVar (9x as pathogenic, 2x as likely pathogenic), LOVD (1x as likely pathogenic, 2x as NA) and CancerHotspots (9 somatic observations). Based on the currently available information, c.542G>A is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 17, 2022	This missense variant replaces arginine with histidine at codon 181 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies reported conflicting findings on variant protein activities in yeast transactivation assays, human cell growth suppression assays, human cell proliferation assay, and TP53 tumor suppressor-associated activities (PMID: 12826609, 20471942, 29979965, 30224644, 34907344; IARC database). The IARC database reports observation of this variant in 12 individuals affected with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (http://mutantp53.broadinstitute.org/). This variant has been reported in multiple individuals affected with early-onset breast cancer and family history of multiple cancers, who meet Chompret criteria for Li-Fraumeni syndrome (PMID: 1591732, 1631137, 21059199, 33818021). A family study has shown this variant to segregate with breast cancer and leiomyosarcoma in three siblings (PMID: 1631137). This variant also has been observed in an individual affected with late-onset adrenocortical carcinoma, pheochromocytoma and glioblastoma multiforme, who had been clinically diagnosed with neurofibromatosis type 1 (PMID: 23175693). This variant has been identified in 4/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg181Cys and p.Arg181Pro, are associated with disease (ClinVar variation ID: 125689 and 59756), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Jul 01, 2023	Data included in classification: UK family: Mother breast cancer at 46, daughter breast cancer at 37, family history of breast cancer, brain tumour and haemangiosarcoma Brand et al 2018: 1 patient Baek et al 2019: 1 patient adrenocortical carcinoma Borresen et al 1992: 1 patient breast cancer at 31yrs Heymann et al 2010: 1 patient breast cancer 29yrs Raymond et al 2013: 1 patient adrenocortical carcinoma GeneDx case (contacted due to ClinVar entry): 1 patient meeting Chompret Ambry genetics (ClinVar entry): 3 patients meet Chompret Color Genetics (ClinVar entry): 1 patient meets Chompret 5.5 points (11 x patients meeting Chompret criteria) (PS4_str). aGVGD score = C25, bayes del 0.258 (PP3_sup). Update July 2023: 9 somatic observations of this variant in cancerhotspots.org (PM1_sup). Data not included in classification: Kato et al, 2003- partially functional (>20 but <75%) Giacomelli et al, 2018 - unclassified (has DNE score but not LOF) Fortuno et al - Bayesdel 0.258 suggested prediction = pathogenic 9 germline cases on IARC 4 heterozygotes in gnomAD non-cancer (v2.1.1) – 3 male, 1 female -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 06, 2024	The p.R181H variant (also known as c.542G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 542. The arginine at codon 181 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in a proband with early-onset breast cancer who also met Chompret criteria for TP53 testing (Borresen A et al. Cancer Res. 1992 Jun 1;52(11):3234-6), in an individual diagnosed with breast cancer at age 29 and a family history of multiple cancers (Heymann S et al. Radiat. Oncol. 2010 Nov 8;5:104), and also in an individual with adrenocortical carcinoma and clinical history of neurofibromatosis type 1 (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan;98(1):E119-25). Functional studies in yeast have shown significant levels of reduced transactivation activity with the p.R181H variant (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Other functional studies have shown that p.R181H causes a defect in promoter binding and transactivation of apoptotic target genes, causing a loss of apoptotic activity (Schlereth K et al. Mol. Cell 2010 May;38(3):356-68; Wang W et al. Genes Dev. 1996 May;10(10):1219-32), but was similar to wild type in that it does not bind proteins specific for the mutant conformation of the p53 protein (Frebourg et al. Proc Natl Acad Sci U.S.A. 1992 Jul;89(14):6413-7), and shows proficient growth suppression in human cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 10;50:1381-1387). This alteration demonstrated a partially reduced ability to bind DNA (Malcikova et al. Biol. Chem. 2010; 391(2-3):197-205). In addition, other missense alterations impacting this codon (p.R181C, p.R181L, and p.R181P) have been reported as associated with TP53-related disease and causing impaired function (Sidransky D et al. Cancer Res. 1992;15;52(10):2984-6; Villani A et al. Lancet Oncol. 2016 Sep;17(9):1295-305; Krutikova V et al. Eur. J. Cancer. 2005 Jul;41(11):1597-603; Kyritsis AP et al. J. Natl. Cancer Inst. 1994 Mar 2;86(5):344-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R181H is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised. -

Li-Fraumeni syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces arginine with histidine at codon 181 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies reported conflicting findings on variant protein activities in yeast transactivation assays, human cell growth suppression assays, human cell proliferation assay, and TP53 tumor suppressor-associated activities (PMID: 12826609, 20471942, 29979965, 30224644, 34907344). Some studies have reports a specific impairment in the transactivation of apoptosis-related genes (PMID: 20471942, 20948308, 34067731, 34907344). The IARC database reports observation of this variant in 12 individuals affected with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (http://mutantp53.broadinstitute.org/). This variant has been reported in multiple individuals affected with breast cancer, several of which presented as early onset, and in individuals who meet Chompret criteria for Li-Fraumeni syndrome (PMID: 1591732, 1631137, 17606709, 21059199, 23175693, 25186627, 28724667, 29522266, 30264118, 30653764, 31060593, 31119730, 33245408, 33471991, 33818021, 34793666, 35626031, 35820297, 35875466, 35884425, 37563628, 38153744, 38201513). This variant also has been observed in an individuals affected with late-onset adrenocortical carcinoma (PMID: 23175693, 30653764). Mulitiple studies have shown this variant to segregate with disease (PMID: 1631137, 30653764, 33245408, 35875466). This variant has been identified in 4/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon are associated with disease (ClinVar Variation ID: 125689, 59756). Although this variant does not appear to present clinically as a classic Li-Fraumeni allele, based on the available evidence this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 181 of the TP53 protein (p.Arg181His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 1591732, 21059199, 1631137, Invitae). A review of approximately 50 individuals with this variant revealed they were less likely to meet clinical criteria for Li-Fraumeni syndrome compared to carriers of other well defined TP53 pathogenic variants (Invitae). This suggests this variant may be associated with varying or atypical clinical presentation. It is commonly reported in individuals of Arabic ancestry (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). ClinVar contains an entry for this variant (Variation ID: 142320). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 12826609, 20128691, 21343334, 29979965, 30224644). This variant disrupts the p.Arg181 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2023	Variant summary: TP53 c.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Five 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 251324 control chromosomes. c.542G>A has been reported in the literature in individuals affected with features of atypical Li-Fraumeni Syndrome and breast cancer (example, Borresen_1992, Heymann_2010, Frebourg_1992, Alyami_2021). An ascertainment of one family with this variant, identified 3 transmissions of the variant allele and 1 transmissions of the reference allele to affected individuals (Frebourg_1992). These data indicate that the variant may be associated with disease. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe deficiency based on the mean transactivation capacity across four different reporter strains (example, Monti_2011). However, another study reported a neutral effect on growth of malignant cells in-vitro with retained structural features of the WT protein and the somatic loss of the mutant allele in a tumor from a family reporting this variant (Frebourg_1992). Multple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 08, 2023	The TP53 c.542G>A (p.Arg181His) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 1591732, 21059199, 23175693, 30067863, internal data). Computational evidence supports a deleterious effect of this variant on protein function and transactivation assays show a partially functioning allele according to Kato et al., and moderate evidence of a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is also a somatic hotspot in tumors. In summary, this variant meets criteria to be classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 23, 2023	The c.542G>A p.(Arg181His) variant in the TP53 gene has previously been reported in multiple individuals with TP53-related cancers such as early-onset breast cancer, adrenocortical carcinoma, leiomyosarcoma, rhabdomyosarcoma, pancreatic adenocarcinoma [PMID: 1591732, 1631137, 21059199,30653764, 28767289, 35512711, TP53 database: https://tp53.isb-cgc.org/results_germline_mutation_list] and segregates with cancer in several affected families [PMID: 1631137, 30653764, 33245408]. It has been deposited in ClinVar [ClinVar ID: 142320] as Likely Pathogenic/Pathogenic. The c.542G>A variant is observed in 6 alleles (~0.001% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.542G>A variant in TP53 is located in exon 5 of this 11-exon gene, and predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 181 in the DNA-binding domain of the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg181His) [(CADD v1.6 = 25.5, REVEL = 0.797)]. Other missense alterations impacting this codon (p.Arg181Cys, p.Arg181Pro) have been reported as associated with TP53-related cancers [PMID: 27501770, 27866339, 28486781, 23484829, 15925506, 29360161]. Based on available evidence this c.542G>Ap.(Arg181His) variant identified in TP53 is classified as Pathogenic. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 04, 2024

- -

Carcinoma of pancreas

Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

Mar 04, 2021

- -

Familial cancer of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

University Health Network, Princess Margaret Cancer Centre

Mar 19, 2021

- -

TP53-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2024

The TP53 c.542G>A variant is predicted to result in the amino acid substitution p.Arg181His. This variant is located at the CpG-site and has been observed (both somatic and germline) in individuals with primary central nervous system lymphoma (Munch-Petersen et al. 2016. PubMed ID: 27101868), adrenocortical carcinoma (Raymond et al. 2013. PubMed ID: 23175693), breast carcinoma (Børresen et al. 1992. PubMed ID: 1591732), and also with Li Fraumeni syndrome (Heymann et al. 2010. PubMed ID: 21059199). This variant has been reported to segregate in a family with varied cancers (Baek et al. 2019. PubMed ID: 30653764). Functional studies on this variant have demonstrated reduced tumor-suppressor activity of p53 (Schlereth et al. 2010, PubMed ID: 20471942); however, there were mixed findings in terms of its effect on the transactivation activity (Malcikova et al. 2010, PubMed ID: 20128691; Monti et al. 2007, Table 1B, PubMed ID: 17606709). Furthermore, several other amino acid substitutions at this position (p.Arg181Pro, p.Arg181Leu, p.Arg181Cys) have been reported in individuals with TP53-related disorders (Monti et al. 2011. PubMed ID: 21343334; Kyritsis et al. 1994. PubMed ID: 8308926; Lolas Hamameh et al. 2017. PubMed ID: 28486781). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD and the majority of labs interpret this variant as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142320/). This variant is interpreted as pathogenic. -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.78

MetaRNN

Uncertain

0.69

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

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

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0050

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

Sift4G

Benign

0.069

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

Polyphen

1.0

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

Vest4

0.58

MVP

0.96

MPC

1.8

ClinPred

0.80

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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