rs1060499561

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.731G>A(p.Gly244Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G244S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a turn (size 5) in uniprot entity P53_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 chr17-7674233-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 17-7674232-C-T is Pathogenic according to our data. Variant chr17-7674232-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7674232-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.731G>A	p.Gly244Asp	missense_variant	7/11	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.731G>A	p.Gly244Asp	missense_variant	7/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 244 of the TP53 protein (p.Gly244Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer, colon cancer, and melanoma (PMID: 16494995, 29470806; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372785). 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, 16494995, 16861262, 21343334, 22319594, 29979965, 30224644). This variant disrupts the p.Gly244 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18511570, 18628487, 24307375, 25925845, 26818906). 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2018	The p.Gly244Asp variant in TP53 has been reported in 4 individuals with TP53-associated cancers (IARC TP53 Database: http://p53.iarc.fr, Achatz 2007, Oden-Gangloff 2009, Zeki 2013) and segregated with disease in 5 affected relatives from 1 family (Achatz 2007). This variant was absent from large population studies, but has been reported in ClinVar, as both a germline and somatic variant (Variation ID: 372785). Amino acid position 244 is a known TP53 mutation hotspot, with several different variants, including p.Gly244Ser and p.Gly244Val, that have been reported in individuals with TP53-associated cancers (Oden-Gangloff 2009, Zeki 2013, Watson 2014, Arcand 2015, Hu 2016, Krutilkova 2005, Monti 2011). In vitro functional studies provide some evidence that the p.Gly244Asp variant may impact protein function (Kato 2003, Monti 2011, Paget 2012). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly244Asp variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PS3_Moderate; PS4_Moderate; PP1_Moderate; PP3. -

Li-Fraumeni syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 16, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Sep 29, 2022	PS4, PP3, PM2_SUP, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Brachmann 1998, Dearth 2007, Monti 2011, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25637035, 27146902, 32980694, 25525159, 9524109, 12909720, 16861262, 8633021, 15825182, 27196127, 24481001, 22178590, 19367287, 23939625, 16494995, 28222664, 28592622, 29413759, 28100260, 28945843, 32817165, 29979965, 29489754, 30076369, 29070607, 30287823, 30720243, 30840781, 15510160, 34529667, 31105275, 21343334) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2024	The p.G244D pathogenic mutation (also known as c.731G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 731. The glycine at codon 244 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in a Brazilian individual diagnosed with breast cancer at 40 years old and colorectal cancer (age unspecified) with a family history of early-onset bone cancer, breast cancer, sarcoma, and cancer of the female genital organs (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196). This variant has also been reported in children with Li-Fraumeni syndrome-related cancers (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180; Grobner S et al. Nature. 2018 03;555(7696):321-327). 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 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). In addition, two alterations at this same position (p.G244S and p.G244V) have been identified in individuals meeting Chompret criteria (Krutilkova V et al. Eur J Cancer. 2005 Jul;41(11):1597-603; Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

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

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.72

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

0.90

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.6

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.90

MutPred

0.99

Loss of catalytic residue at G244 (P = 0.1492);Loss of catalytic residue at G244 (P = 0.1492);.;.;.;.;.;.;.;Loss of catalytic residue at G244 (P = 0.1492);.;Loss of catalytic residue at G244 (P = 0.1492);Loss of catalytic residue at G244 (P = 0.1492);Loss of catalytic residue at G244 (P = 0.1492);.;.;Loss of catalytic residue at G244 (P = 0.1492);.;.;.;.;

MVP

0.99

MPC

0.44

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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