chr17-7674216-C-A

Variant names:

• chr17-7674216-C-A
• rs28934571
• NM_000546.6:c.747G>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.747G>T​(p.Arg249Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: -1.47

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-7674216-C-A is Pathogenic according to our data. Variant chr17-7674216-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.747G>T	p.Arg249Ser	missense_variant	Exon 7 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.747G>T	p.Arg249Ser	missense_variant	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 249 of the TP53 protein (p.Arg249Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni Syndrome (PMID: 30374176). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12352). 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: 9407971, 15982667, 16754663, 19913028, 20516128, 20538734, 22110706, 25131192). 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. -

May 25, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The TP53 variant designated as NM_000546.5:c.747G>T (p.Arg249Ser) is classified as pathogenic. This variant has not been reported in public population databases. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 7.52 to 1 that this allele explains cancer in the family (Thompson et al, 2003, PMID:2900794). Computer software programs (SIFT, Polyphen-2, PROVEAN) predict that this variant is likely to have a damaging effect. Experimental functional studies provide evidence that this variant can lead to loss of function by disrupting protein structure (Gouas et al, 2010, PMID: 20538734; Lee et al, 2008, PMID: 18477611; Butler et al, 2005, PMID: 15982667; Joerger et al, 2005, PMID: 15703170; Chan et al, 2004, PMID:15060172; Kato et al, 2003, PMID: 12826609; Bullock et al, 1997, PMID: 9405613). Additionally, analysis of breast tumor in one member of the observed family shows loss of heterozygosity for the allele with this TP53 variant in breast tissue, which adds moderate evidence that this variant is pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 99% probability of pathogenicity, which is consistent with a classification of pathogenic. The combined results are consistent with a classification of pathogenic in the context of Li-Fraumeni syndrome. This variant is expected to alter TP53 function and increase risks related to Li-Fraumeni syndrome associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 16, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with serine at codon 249 of the TP53 protein. Codon 249 is a known mutational hotspot for somatic mutation in cancer (PMID: 15982667, 17311302, 19756158, 28412734, 33300245). 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 have shown that this variant to be defective in yeast-based transcriptional transactivation assays, and human cell proliferation and growth suppression assays (PMID: 12826609, 29979965, 30224644). This variant has been reported germline in individuals affected with early onset breast cancer (PMID: 30374176; Color internal data) and is reported at high frequency as a somatic mutation in Aflatoxin B1- and Hepatitis B virus-related hepatocellular carcinoma (PMID: 20182602, 30508182, 30608603). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jul 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R249S pathogenic mutation (also known as c.747G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 747. The arginine at codon 249 is replaced by serine, an amino acid with dissimilar 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 deficient at growth suppression and has a 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). Another alteration at the same codon, p.R249K (c.746G>A), has been detected in one child with adrenal cortical carcinoma (Ambry internal data). The p.R249S alteration was classified as pathogenic 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 has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This alteration has also been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ovarian neoplasm Pathogenic:2

Mar 19, 2021

University Health Network, Princess Margaret Cancer Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Li-Fraumeni syndrome 1 Pathogenic:1

Feb 16, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8001119, 8843196, 12509279, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Adrenal cortex carcinoma Pathogenic:1

-

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cervical cancer Pathogenic:1

May 02, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17332323, 16861262, 9627118, 20538734, 19366907, 23200676, 19376640, 24489544, 21869931, 23836507, 21768053, 22675488, 14741214, 19834951, 18477611, 22759751, 21445056, 27698932, 1349102, 1849234, 8174105, 7935394, 20407015, 27346245, 17344317, 10321740, 8843196, 15781620, 32475984, 15982667, 34282142, 20212049, 30224644, 19913028, 34326862, 34273903, 29979965, 15510160, 30374176) -

Hepatocellular carcinoma Pathogenic:1

May 02, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

-

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D
M_CAP	Pathogenic	0.84	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
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.3	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	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;.;.;.
Vest4		0.96
MutPred		0.95		Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);.;.;.;.;.;.;.;Loss of stability (P = 0.0441);.;Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);.;.;Loss of stability (P = 0.0441);.;.;.;
MVP		0.99
MPC		0.40
ClinPred		0.99	D
GERP RS		-0.093
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.90

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

Other links and lift over

dbSNP: rs28934571; hg19: chr17-7577534; COSMIC: COSV52661594; COSMIC: COSV52661594;