chr17-7674252-C-T

Position:

chr17-7674252-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS3PS4PM6_SupportingPM1PP1_Moderate

This summary comes from the ClinGen Evidence Repository: This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID:12826609, 30224644). This variant has been reported in 1 proband meeting Classic LFS criteria and 4 probands meeting Chompret criteria (PS4; PMID:11370630, 25945745, NIH, Invitae, Ambry). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; NIH, Invitae). There is one de novo observation in a proband with breast and thyroid cancer in her 30s without parental confirmation (PM6_Supporting; GeneDx). In summary, TP53 c.711G>A (p.Met237Ile) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4, PP1_Moderate, PM6_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000349/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

12

5

2

Clinical Significance

Pathogenic reviewed by expert panel P:9U:1O:1

Conservation

PhyloP100: 7.83

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 Pathogenic. Variant got 13 ACMG points.

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.

PM6

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

PP1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.711G>A	p.Met237Ile	missense_variant	7/11	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.711G>A	p.Met237Ile	missense_variant	7/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

1

AN:

151834

Hom.:

0

Cov.:

30

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

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251484

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461630

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

727130

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

AF:

0.00000658

AC:

1

AN:

151952

Hom.:

0

Cov.:

30

AF XY:

0.0000135

AC XY:

1

AN XY:

74278

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:

0.00000378

ExAC

AF:

0.00000824

AC:

1

Asia WGS

AF:

0.000289

AC:

1

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:3

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: 9635828, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 12, 2024	Criteria applied: PS3,PS4,PM1,PP1_MOD -
Pathogenic, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Apr 20, 2021	This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 1 proband meeting Classic LFS criteria and 4 probands meeting Chompret criteria (PS4; PMID: 11370630, 25945745, NIH, Invitae, Ambry). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; NIH, Invitae). There is one de novo observation in a proband with breast and thyroid cancer in her 30s without parental confirmation (PM6_Supporting; GeneDx). In summary, TP53 c.711G>A (p.Met237Ile) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4, PP1_Moderate, PM6_Supporting. -

Li-Fraumeni syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Ile). This variant is present in population databases (rs587782664, gnomAD 0.006%). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 11370630; Invitae). ClinVar contains an entry for this variant (Variation ID: 142714). 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: 11370630, 12826609, 17606709, 21343334, 29979965, 30224644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 23, 2023

- -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2020

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: 31105275, 30840781, 30720243, 30309854, 30216591, 29979965, 28669404, 26787237, 26479578, 27492616, 27895743, 27815358, 23967324, 28029553, 26771088, 26563132, 27347849, 27989700, 28222664, 27074569, 27869737, 28057436, 27657329, 27792260, 21512767, 27059324, 25302557, 7651740, 20080630, 9635828, 12509970, 11166732, 18038118, 7718482, 11238194, 14559903, 20407015, 16492679, 15161705, 9546439, 1915267, 16322298, 10713666, 7588628, 21343334, 17606709, 11370630, 16861262, 12826609) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2022

The p.M237I pathogenic mutation (also known as c.711G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 711. The methionine at codon 237 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported as a germline alteration in a classic LFS case (Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48:610-5) as well as in one Li-Fraumeni-like family, and identified in multiple individuals meeting Chompret criteria (Bougeard G et al. J Med Genet. 2001 Apr;38(4):253-7; Ambry Internal Data). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: 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 (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Several other in vitro studies have shown that the p.M237I alteration is dominant negative and results in a severe deficiency of p53 transactivation activity, causes radio-resistance with increased frequency of spontaneous and radiation-induced mutations and loss of the ability to inhibit DNA synthesis (Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98; Little JB et al. J Biol Chem. 1995 May12;270(19):11033-6; Vousden KH et al. J Gen Virol. 1993 May;74 (Pt 5):803-10; Wiese C et al. Cancer Res. 2001 Feb 1;61(3):1129-37). Based on internal structural analysis, p.M237I disrupts important hydrogen bonding interactions and the local structure of a functionally important loop near a zinc-binding motif within the DNA binding site of TP53 (Ambry internal data; Golovenko D et al. Structure. 2018 Sep 4;26(9):1237-1250; Lukman S et al. PLoS One. 2013 Nov 12;8(11); Butler JS and Loh SN. Biochemistry. 2003 Mar 4;42(8):2396-403; Bullock AN, Henckel J, Fersht AR. Oncogene. 2000 Mar 2;19(10):1245-56). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

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

0.36

D

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Benign

0.84

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

M_CAP

Pathogenic

0.83

D

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

D

MutationAssessor

Pathogenic

3.3

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.72

T

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0080

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

0.95

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;.;.;.;.;Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);.;.;.;.;

MVP

0.96

MPC

0.40

ClinPred

0.99

D

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587782664; hg19: chr17-7577570; COSMIC: COSV52661887; COSMIC: COSV52661887;