17-7673836-C-T

Position:

chr17-7673836-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor (SCV000686773.2). In summary, the clinical significance of TP53 c.784G>A (p.Gly262Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000416/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense, splice_region

Scores

Splicing: ADA: 0.9760

Clinical Significance

Uncertain significance reviewed by expert panel U:9O: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

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

BS2

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.784G>A	p.Gly262Ser	missense_variant, splice_region_variant	8/11	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.784G>A	p.Gly262Ser	missense_variant, splice_region_variant	8/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000817

AC:

AN:

244722

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132322

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1459598

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725972

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:

0.0000279

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2023	This missense variant replaces glycine with serine at codon 262 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 conflicting for this variant with the variant shown to be defective for transcriptional transactivation in yeast (PMID: 12826609) but functional in human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 26534844, 32095738). This variant has been identified in 3/276106 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2023	The p.G262S variant (also known as c.784G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 784. The glycine at codon 262 is replaced by serine, an amino acid with similar properties. 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 proficient at growth suppression and has no 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 alteration has been reported in a BRCA1/2-negative woman diagnosed with breast cancer at age 42 and in her unaffected sister (Li J et al. J Med Genet. 2016 Jan;53(1):34-42) and also in a proband with breast cancer diagnosed at age 46 and 56 who underwent multigene panel testing (Bradbury AR et al. JCO Precis Oncol 2018 Apr;2). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 262 of the TP53 protein (p.Gly262Ser). This variant is present in population databases (rs200579969, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 141228). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 04, 2020	This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor (SCV000686773.2). In summary, the clinical significance of TP53 c.784G>A (p.Gly262Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3, BS2_Supporting. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2024	Published functional studies are conflicting: non-functional transactivation, no effect on growth suppression (PMID: 29979965, 12826609, 30224644); Observed in an individual with breast cancer and her unaffected sister (PMID: 26534844); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8023157, 12826609, 7955036, 16907706, 10719737, 11161397, 14670539, 14559903, 9719952, 22768918, 22678923, 27564104, 20025891, 16818665, 31016814, 30840781, 30352134, 29979965, 30224644, 35328131, 30661751, 34273903, 32014905, 15510160, 26534844) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2016	Variant summary: The TP53 c.784G>A (p.Gly262Ser) variant involves the alteration of a conserved nucleotide located in the DNA binding domain, which is the target of 90% of p53 mutations found in human cancers (UMD database). 5/5 in silico tools predict a damaging outcome for this variant. This variant has been reported one family with multiple breast cancer patients, however, no detailed co-segregation analysis was performed. This variant has also been reported in numerous types of tumor samples with or without confirmed somatic status. This variant is absent in 89212 control chromosomes from ExAC. A reputable database (IARC) has reported this variant to have median transcription activity <=20% and classified it as non-functional. Other nearby missense variants have also been reported, namely p.Asn263Asp, p.Gly266Val and p.Arg267Trp; they all have been reported by a lab in ClinVar, the former two classified as uncertain significance and the last as likely pathogenic. One clinical diagnostic laboratory classified this variant as VUS. Taken together, this variant is currently classified as VUS-possibly pathogenic. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2024

- -

TP53-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2024

The TP53 c.784G>A variant is predicted to result in the amino acid substitution p.Gly262Ser. This variant has been reported in an individual with breast cancer as well as in an unaffected sibling (Figure 1, Li et al. 2016. PubMed ID: 26534844). An in silico quantitative model predicts this variant to be pathogenic (Table S1, Fortuno et al. 2019. PubMed ID: 30840781), but has also been predicted to be a variant of uncertain significance by another group (Evans et al. 2019. PubMed ID: 31016814). This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and has been reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141228/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Li-Fraumeni syndrome 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 09-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

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

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.8

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

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.3

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

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0040

D;T;T;T;T;T;T;D;D;D;D;D;D;D;D;D;D;D;T

Polyphen

1.0, 1.0, 0.95

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

Vest4

0.89

MVP

0.99

MPC

0.38

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.52

Position offset: -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