chr17-7675071-G-A

Variant names:

• chr17-7675071-G-A
• rs587782596
• NM_000546.6:c.541C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000546.6(TP53):​c.541C>T​(p.Arg181Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 O:1
• Conservation: PhyloP100: 6.35
• Publications: 167 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 33 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 28 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7675070-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39420.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-7675071-G-A is Pathogenic according to our data. Variant chr17-7675071-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142624.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.541C>T	p.Arg181Cys	missense	Exon 5 of 11	NP_000537.3
	TP53	NM_001126112.3		c.541C>T	p.Arg181Cys	missense	Exon 5 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.541C>T	p.Arg181Cys	missense	Exon 6 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.541C>T	p.Arg181Cys	missense	Exon 5 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.541C>T	p.Arg181Cys	missense	Exon 5 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.424C>T	p.Arg142Cys	missense	Exon 4 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 16, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R181C variant (also known as c.541C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 541. The arginine at codon 181 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in one individual diagnosed with breast cancer at age 33 and melanotic spindle cell carcinoma of the mediastinum at age 35 and in another individual with rhabdomyosarcoma, adrenal cortical carcinoma, and osteosarcoma (Sidransky D et al. Cancer Res. 1992;15;52(10):2984-6; Villani A et al. Lancet Oncol. 2016 Sep;17(9):1295-305). In addition, one study found this alteration in six family members ranging in age from 16 to 60; however, only two of them were affected with cancer (Wang PY et al. N. Engl. J. Med. 2013;368(11):1027-32). This alteration has more recently been reported in several families that have multiple early-onset cancers but do not meet Li-Fraumeni syndrome criteria, although some met Chrompret criteria, leading the authors to suggest this is a pathogenic mutation with an attenuated phenotype (Zick A et al. Fam. Cancer. 2017 Apr;16:295-301; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). Yeast based functional studies have shown this alteration to have significantly reduced transactivation capacity compared to wild type, as well as dominant negative properties with several response elements (Monti P et al. Mol Cancer Res. 2011;9(3):271-9; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003;8;100(14):8424-9). However, this alteration showed DNA binding activity similar to wild type (Malcikova J et al. Biol. Chem.;391:197-205), and was proficient at growth suppression in human cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). A different alteration which occurs at the same codon, p.R181H (c.542G>A) has been seen in individuals with breast cancer and Li-Fraumeni syndrome (Heymann S et al. Radiat Oncol. 2010;5:10; Børresen AL et al. Cancer Res. 1992;52(11):3234-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R181C is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised.

Dec 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine 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 are inconsistent about the variant impact on TP53 protein function. While some studies have shown that the mutant protein shows partial reduction of transactivation activity (IARC database and PMID: 12826609) and normal function in human cell growth suppression assays (PMID: 29979965, 30224644), other studies have shown that this variant partially or fully impairs transcriptional transactivation activity, DNA binding activity, and apoptotic activity of the TP53 protein (PMID: 10229196, 12917626, 17606709, 20128691, 20471942, 21343334). Transgenic mice homozygous for a homolog of this variant showed a slight increase in tumorigenesis (PMID: 31968253). This variant has been reported in multiple individuals suspected of having Li-Fraumeni syndrome or affected with Li-Fraumeni syndrome-associated tumors (PMID: 17606709, 27501770, 27866339, 35033608), including an adult affected with glioblastoma multiform at 70 years old (PMID: 27866339) and a child affected with rhabdomyosarcoma, adrenocortical carcinoma and osteosarcoma, who died at age 3 years old (PMID: 27501770). This variant has been reported in over 15 individuals affected with breast cancer, most of whom showed early-onset with family history of breast cancer or other Li-Fraumeni syndrome-associated tumors (PMID: 1581912, 27866339, 28486781, 31119730, 33471991). Among the reported breast cancer-affected females, four of them showed age of onset prior to age 31 years old (PMID: 27866339, 28486781). This variant has been shown to segregate with breast cancer in six individuals from two families of Arab ancestry, where incomplete penetrance was observed (PMID: 28486781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant p.Arg181His occurring at the same codon is known to be pathogenic, based on the observation in multiple individuals affected with Li-Fraumeni syndrome-associated tumors, who showed strong family history (Clinvar variation ID: 142320). This indicates that arginine at the codon 181 position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. This variant may be hypomorphic and may display reduced penetrance relative to typical pathogenic TP53 variants.

not provided Pathogenic:1 Uncertain:1

Jul 21, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies are inconclusive: conflicting transactivation results, growth suppression ability similar to wild-type, retained or reduced DNA binding abilities, reduced apoptotic activity (Smith 1999, Campomenosi 2001, Monti 2002, Kato 2003, Boutell 2004, Gohler 2005, Schlereth 2010, Malcikova 2010, Monti 2011, Giacomelli 2018, Kotler 2018, Kang 2020); Observed in individuals with breast and other Li-Fraumeni-associated cancers; however, multiple unaffected carriers and at least one homozygous individual have also been reported (Sidransky 1992, Monti 2007, Wang 2013, Kwong 2016, Villani 2016, Lolas Hamameh 2017, Zick 2017, Chan 2018, Sheng 2019, Kwong 2020); Demonstrated incomplete segregation with breast cancer diagnoses in a large Middle Eastern breast cancer kindred (Lolas Hamameh 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 34067731, 33230179, 32722340, 32322110, 34240179, 32303989, 32075053, 33138793, 15510160, 31105275, 27535533, 31119730, 27501770, 31968253, 20471942, 30840781, 30093976, 30720243, 29979965, 28611940, 29086229, 28736647, 28828701, 27866339, 1581912, 14559903, 15221755, 15722483, 11429705, 11896595, 15603511, 26366557, 26887044, 19367569, 28222664, 26771088, 28486781, 27157322, 15077144, 11358831, 17914575, 15580553, 21343334, 20128691, 17606709, 10229196, 23484829, 30224644)

Li-Fraumeni syndrome Pathogenic:1

Jan 27, 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 cysteine, which is neutral and slightly polar, at codon 181 of the TP53 protein (p.Arg181Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni like syndrome or individual(s) who meet Chrompret criteria (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). This variant has not been observed in individual(s) with Li-Fraumeni syndrome. It is commonly reported in individuals of Arab ancestry (PMID: 27866339, 28486781). ClinVar contains an entry for this variant (Variation ID: 142624). 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: 11896595, 12826609, 12917626, 17606709, 20471942, 21343334). 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: 1591732, 11429705, 20128691, 21059199, 21343334, 23175693). 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.

Adrenocortical carcinoma, hereditary Pathogenic:1

May 03, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Pathogenic:1

May 06, 2024

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

TP53 p.R181C (c.641C>T) was identified in 25 breast cancer patients of Palestinian ancestry. The variant co-segregates with breast cancer in their families, with a lifetime risk to heterozygous females of 81% (s.e. 9%) (PMID: 28486781). Only one of the 25 families fulfilled criteria for Li-Fraumeni syndrome. Across all 25 families, pediatric cancers (diagnosed by age 20y) were not more frequent among first degree relatives of p.R181C-heterozygous breast cancer patients compared to first degree relatives of unrelated age-matched Palestinian breast cancer patients with no pathogenic variant (RR = 0.90, 95% CI [0.23, 3.49]; in-house data). Based on current evidence, p.R181C is interpreted as pathogenic but with risk limited to breast cancer

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.015	D
Polyphen		0.77	P
Vest4		0.71
MutPred		0.93		Gain of catalytic residue at S183 (P = 0.0137)
MVP		0.98
MPC		1.3
ClinPred		0.96	D
GERP RS		5.5
PromoterAI		-0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.42
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587782596; hg19: chr17-7578389; COSMIC: COSV52689134; COSMIC: COSV52689134;