17-7676224-C-T

Position:

chr17-7676224-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM2_SupportingBS2BP4BS3

This summary comes from the ClinGen Evidence Repository: The NM_000546.6 :c.145G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 49 (p.Asp49Asn). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; ClinVar SCV: SCV000216702.6). This variant has an allele frequency of 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.232; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000056/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:7

Conservation

PhyloP100: 0.360

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 Benign. Variant got -8 ACMG points.

PM2

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

BP4

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

BS2

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

BS3

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.145G>A	p.Asp49Asn	missense_variant	4/11	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.145G>A	p.Asp49Asn	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251366

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

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:

0.0000130

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

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

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 49 of the TP53 protein (p.Asp49Asn). This variant is present in population databases (rs587780728, gnomAD 0.01%). This missense change has been observed in individual(s) with mesothelioma and skin cancer (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 186363). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 05, 2024	The NM_000546.6 :c.145G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 49 (p.Asp49Asn). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; ClinVar SCV: SCV000216702.6). This variant has an allele frequency of 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.232; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 12, 2024	The missense variant NM_000546.6(TP53):c.145G>A (p.Asp49Asn) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 186363 as of 2024-10-03). There is a small physicochemical difference between aspartic acid and asparagine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Asp49Asn variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Asp49Asn missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The asparagine residue at codon 49 of TP53 is present in Chinese hamster and 1 other mammalian species. The nucleotide c.145 in TP53 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2024	Variant summary: TP53 c.145G>A (p.Asp49Asn) results in a conservative amino acid change located in the Cellular tumor antigen p53, transactivation domain 2 (IPR040926) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 1613988 control chromosomes, predominantly at a frequency of 4.5e-05 within the East Asian subpopulation in the gnomAD database. c.145G>A has been reported in the literature in individuals affected with skin cancer or considered at high risk of breast cancer without strong evidence of causality (e.g. De Rienzo_2016, Su_2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Publications report experimental evidence evaluating an impact on protein function (e.g. Kato_2003, Leroy_2014, Giacomelli_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24665023, 30224644, 26554828, 23525797, 12826609, 22797305, 34917121). ClinVar contains an entry for this variant (Variation ID: 186363), and a ClinGen expert panel has classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0064

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.013

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

2.0

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

PrimateAI

Benign

0.36

PROVEAN

Benign

0.19

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

REVEL

Benign

0.23

Sift

Benign

0.076

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

Sift4G

Benign

0.25

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

Polyphen

0.96

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

Vest4

0.17

MVP

0.87

MPC

0.63

ClinPred

0.080

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.28

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.

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