17-7670684-C-T

Position:

chr17-7670684-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PM2_SupportingBP4BS2_SupportingBS3

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.1025G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 342 (p.Arg342Gln). 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). This variant has been observed in 2-3 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_Supporting; SCV000277448.6). Computational predictor scores (BayesDel =-0.2779; 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). This variant has an allele frequency of 0.000006780 (8/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BS2_Supporting, BP4_Moderate, PM2_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000835/MONDO:0007903/009

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:5

Conservation

PhyloP100: -0.406

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 Likely_benign. Variant got -5 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.1025G>A	p.Arg342Gln	missense_variant	10/11	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.1025G>A	p.Arg342Gln	missense_variant	10/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250992

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

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:

0.00000616

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces arginine with glutamine at codon 342 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental functional studies have shown this variant demonstrates DNA binding, tetramerization, transcriptional activation, and growth suppression activities similar to that of wild-type TP53 (PMID: 9766574, 12826609, 19454241, 20978130, 30224644). Another variant at the same amino acid position (p.Arg342Pro) has been shown to be deficient in these activities, indicating the amino acid position may be important for TP53 function. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 24549055). This variant has been identified in 2/250992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 06, 2024	The NM_000546.6: c.1025G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 342 (p.Arg342Gln). 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). This variant has been observed in 2-3 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_Supporting; SCV000277448.6). Computational predictor scores (BayesDel =-0.2779; 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). This variant has an allele frequency of 0.000006780 (8/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BS2_Supporting, BP4_Moderate, PM2_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 21, 2023	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. This variant disrupts the p.Arg342 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9766574, 10064694, 16007150, 19454241, 19806023, 20978130, 25226867, 25981898). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 342 of the TP53 protein (p.Arg342Gln). This variant is present in population databases (rs375338359, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 233136). 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 9766574, 12826609). -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 31, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 24, 2021	This missense variant replaces arginine with glutamine at codon 342 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental functional studies have shown this variant demonstrates DNA binding, tetramerization, transcriptional activation, and growth suppression activities similar to that of wild-type TP53 (PMID: 9766574, 12826609, 19454241, 20978130, 30224644). Another variant at the same amino acid position (p.Arg342Pro) has been shown to be deficient in these activities, indicating the amino acid position may be important for TP53 function. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 24549055). This variant has been identified in 2/250992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2022	Variant summary: TP53 c.1025G>A (p.Arg342Gln) results in a conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250992 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1025G>A has been reported in the literature as a VUS in settings of multigene panel testing for hereditary breast and ovarian cancer (example, Castera_2014) and as a somatic variant in a variety of tumor settings (COSMIC database, Ten Broeke_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At-least one co-occurrence with another inferred germline pathogenic variant(s) has been reported in an individual with colorectal cancer and a characteristic MSH2-negative/MSH6-negative IHC pattern (Ten Broeke_2018, MSH2 c.1413del, p.Lys471fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Rollenhagen_1998, Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Multiple clinical diagnostic laboratories and an expert panel (ClinGen TP53 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 reporting the variant with conflicting assessments (likely benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast and/or ovarian cancer in published literature (Castera 2014); Published functional studies demonstrate no damaging effect: oligomerization, transcription activity, and DNA binding activity similar to wild type (Rollenhagen 1998, Kato 2003, Imagawa 2009); This variant is associated with the following publications: (PMID: 10499619, 28993836, 14559903, 24549055, 9766574, 20978130, 19454241, 24665023, 28861920, 30840781, 25226867, 12826609, 30224644) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

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

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.064

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.063

MetaRNN

Benign

0.095

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

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.2

.;.;.;L;.;L;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.46

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

REVEL

Benign

0.10

Sift

Benign

0.23

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

Sift4G

Benign

0.35

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

Polyphen

0.061

.;.;.;B;.;B;.;.

Vest4

0.12

MVP

0.79

MPC

0.076

ClinPred

0.22

GERP RS

2.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.14

gMVP

0.38

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