17-7673703-C-T

Position:

chr17-7673703-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The ENST00000269305.9(TP53):c.917G>A(p.Arg306Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R306G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense, splice_region

Scores

Splicing: ADA: 0.001090

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 4.03

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_pathogenic. Variant got 8 ACMG points.

PM1

In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 513 pathogenic changes around while only 147 benign (78%) in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.917G>A	p.Arg306Gln	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.917G>A	p.Arg306Gln	missense_variant, splice_region_variant	8/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251484

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 306 of the TP53 protein (p.Arg306Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, appendiceal adenocarcinoma, and/or lung cancer (PMID: 19930417, 30374176, 35033608). ClinVar contains an entry for this variant (Variation ID: 458574). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	This missense variant replaces arginine with glutamine at codon 306 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant displays partial function in yeast transcription transactivation assays and is functional in human cell growth suppression assays (PMID: 12826609, 30224644). This variant has not been reported in individuals affected with lung, apendiceal and ovarian cancers (PMID: 19930417, 35033608) but also in unaffected individuals (PMID: 33471991). This variant has been identified in 1/251484 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, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Mar 28, 2018	The TP53 variant designated as NM_000546.5:c.917G>A (p.Arg306Gln) is classified as likely benign in the context of Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (RaÃ±ola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.05 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. The variant is at a moderately conserved genomic position. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign in the context of Li-Fraumeni syndrome. However, loss of heterozygosity was seen in the tumor of an affected individual with breast cancer in this observed family, which provides some evidence for pathogenicity with regard to the individual's breast cancer. We cannot rule out the possibility that this variant may cause some increased risk for breast cancer or other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 25490678, 19930417, 30374176, 30352134, 25925845, 35033608, 30224644, 27866339, 34273903, 35534704, 33471991, 32554555) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	The frequency of this variant in the general population, 0.000004 (1/251484 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 19930417 (2010)). Experimental results on protein function were inconclusive (PMIDs: 30352134 (2019), 30224644 (2018), 12826609 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 23, 2024	The p.R306Q variant (also known as c.917G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 917. The arginine at codon 306 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an ovarian cancer patient and in a pediatric AML patient (Blanco A et al. Clin Genet. 2010 Feb;77(2):193-6; Fenwarth L et al. Haematologica, 2021 03;106:908-912). This variant was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was classified as likely benign by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This variant 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 (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 21, 2019	This missense variant replaces arginine with glutamine at codon 306 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that the variant impairs the transactivation activity of the TP53 protein (PMID: 12826609 and IARC database). This variant has been reported in an individual affected with ovarian cancer (PMID: 19930417). This variant has also been identified in 1/251484 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 23, 2023

Variant summary: TP53 c.917G>A (p.Arg306Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.917G>A has been reported in the literature in individuals affected breast- and ovarian cancer (e.g. Blanco_2010, Tsai_2019), and with various tumor phenotypes that belong to the Li-Fraumeni Syndrome tumor spectrum (e.g. Fenwarth_2020, Tian_2022), however it was also reported in unaffected controls (e.g. Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC TP53 database reports this variant to be non- functional based on transcriptional activity in yeast (Kato_2003). However, a loss-of-function saturation mutagenesis screen performed in in human cell lines indicated that this missense doesn't substantially affect TP53 function (Giacomelli_2018). In addition, a multifactorial probability model predicted this variant to be a VUS (Fortuno_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19930417, 30374176, 32554555, 33471991, 35033608, 12826609, 30224644, 34273903). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 07, 2023

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

Jun 13, 2017

The TP53 variant designated as NM_000546.5:c.917G>A (p.Arg306Gln) is classified as variant of uncertain significance in the context of famiial breast cancer. Loss of heterozygosity was seen in the tumor of an affected individual with breast cancer in one family, which provides evidence for pathogenicity. Some TP53 missense variants have been associated with somewhat increased risk of breast cancer, but do not cause the high cancer risk associated with truncating TP53 variants (Giacomazzi et al., 2014, PMID:24936644; Arcand et al., 2015, PMID:25925845; Zick et al., 2016, PMID:27866339). Exact breast cancer penetrance for these variants has not been established. For the TP53 p.Arg306Gln variant, family co-segregation analysis assuming low penetrance gives a likelihood ratio of 0.34 using the Thompson et al. cosegregation method (PMID:12900794). This likelihood ratio is less than one, indicating that the variant is less likely to be associated with breast cancer risk. The TP53 p.Arg306Gln variant has not previously been reported in ClinVar. It is at a moderately conserved genomic position. A modest increase in breast cancer risk due to this variant cannot be entirely excluded. This variant is considered a variant of uncertain significance in the context of breast cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Squamous cell carcinoma of the head and neck

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

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

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

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

MutationTaster

Benign

0.98

D;D;D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

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

REVEL

Pathogenic

0.76

Sift

Uncertain

0.018

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

Sift4G

Benign

0.067

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

Polyphen

0.93, 0.44, 1.0

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

Vest4

0.45

MutPred

0.74

Loss of helix (P = 0.1706);.;.;.;.;.;.;.;Loss of helix (P = 0.1706);.;Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;.;Loss of helix (P = 0.1706);.;.;.;

MVP

0.93

MPC

0.13

ClinPred

0.61

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0011

dbscSNV1_RF

Benign

0.050

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