17-7675071-G-A

Position:

chr17-7675071-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 6.35

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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

PM2

Very rare variant in population databases, with high coverage;

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 id is 142624.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.541C>T	p.Arg181Cys	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.541C>T	p.Arg181Cys	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2024	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. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2021	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 21, 2023	- -

Li-Fraumeni syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

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). 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. 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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 03, 2023

- -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

King Laboratory, University of Washington

May 06, 2024

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

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

Benign

2.0

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

D;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.015

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

Polyphen

0.77

P;.;.;.;.;.;.;.;.;B;.;B;D;B;.;.;B;.;.;.;P

Vest4

0.71

MutPred

0.93

Gain of catalytic residue at S183 (P = 0.0137);Gain of catalytic residue at S183 (P = 0.0137);.;.;.;.;.;.;.;Gain of catalytic residue at S183 (P = 0.0137);.;Gain of catalytic residue at S183 (P = 0.0137);Gain of catalytic residue at S183 (P = 0.0137);Gain of catalytic residue at S183 (P = 0.0137);.;.;Gain of catalytic residue at S183 (P = 0.0137);.;.;.;.;

MVP

0.98

MPC

1.3

ClinPred

0.96

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.76

gMVP

0.42

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

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

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