17-7673796-C-T

Variant names:

• chr17-7673796-C-T
• rs863224451
• NM_000546.6:c.824G>A

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.824G>A​(p.Cys275Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.91

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 DNA (size 7) in uniprot entity P53_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-7673796-C-T is Pathogenic according to our data. Variant chr17-7673796-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673796-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.824G>A	p.Cys275Tyr	missense_variant	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.824G>A	p.Cys275Tyr	missense_variant	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461830 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74254

Gnomad4 AFR AF: 0.0000242

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Mar 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 275 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). Experimental studies have shown that this variant disrupted function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with Li-fraumeni syndrome (PMID: 7887414, 14584079; ClinVar SCV000253702.9) and early-onset breast cancer meeting Chompret criteria (PMID: 33818021, 34793666, 35127508). In at least two families, this variant co-segregated with Li-fraumeni syndrome (PMID: 7887414, 14584079). This variant has also been reported in chronic lymphocytic leukemia (PMID: 19850740, 21232794, 22983585), and other cancers (PMID: 11051239, 26425688). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.824G>T (p.Cys275Phe), is considered to be disease-causing (ClinVar Variation ID: 376582), suggesting that cysteine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C275Y pathogenic mutation (also known as c.824G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 824. The cysteine at codon 275 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation was identified as a germline alteration in three individuals from a family with Li-Fraumeni syndrome (LFS), where the proband had a rhabadomyosarcoma at 2 years of age, the father with sarcoma at 34y, and a paternal uncle with sarcoma at 22y and 27y (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15). This mutation has also been identified as a germline alteration in a separate LFS family, where 16 family members had 18 sarcomas of various types, as well as breast cancer and leukemia (Lynch HT et al. Cancer. 2003 Nov 1;98(9):1947-57). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative effect in yeast-based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P, Mol. Cancer Res. 2011 Mar; 9(3):271-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression in vitro (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 observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). In addition, residue 275 of the p53 protein has been shown by crystal structure to be involved in DNA contact (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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. -

Li-Fraumeni syndrome 1 Pathogenic:2

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 14584079]. -

Li-Fraumeni syndrome Pathogenic:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 275 of the TP53 protein (p.Cys275Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic lymphocytic leukemia and Li-Fraumeni syndrome (PMID: 7887414, 14584079, 17606709, 19850740; internal data). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215997). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. -

May 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 275 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). Experimental studies have shown that this variant disrupted function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with Li-fraumeni syndrome (PMID: 7887414, 14584079; ClinVar SCV000253702.9) and early-onset breast cancer meeting Chompret criteria (PMID: 33818021, 34793666, 35127508). In at least two families, this variant co-segregated with Li-fraumeni syndrome (PMID: 7887414, 14584079). This variant has also been reported in chronic lymphocytic leukemia (PMID: 19850740, 21232794, 22983585), and other cancers (PMID: 11051239, 26425688). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.824G>T (p.Cys275Phe), is considered to be disease-causing (ClinVar Variation ID: 376582), suggesting that cysteine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Moderate -

Apr 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation with a dominant-negative effect, loss of growth suppression and apoptotic activities (Flaman 1998, Waddell 2001, Kato 2003, Bergamaschi 2003, Monti 2011, Kotler 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12726864, 30720243, 9546439, 29979965, 31105275, 17606709, 21343334, 9115587, 8458321, 11593407, 10519380, 12826609, 29489754, 30840781, 14584079, 7887414, 15138567, 15541116, 33818021) -

Adrenocortical carcinoma, hereditary Pathogenic:1

Jun 08, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian neoplasm Pathogenic:1

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

- -

Breast carcinoma Pathogenic:1

Sep 04, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Acute myeloid leukemia Pathogenic:1

-

Ayesha Lab, University of the Punjab

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;D;D;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-10	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	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
Polyphen		1.0	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.98
MutPred		0.98		Gain of phosphorylation at C275 (P = 0.0364);.;.;.;.;.;.;.;Gain of phosphorylation at C275 (P = 0.0364);.;Gain of phosphorylation at C275 (P = 0.0364);Gain of phosphorylation at C275 (P = 0.0364);Gain of phosphorylation at C275 (P = 0.0364);.;.;Gain of phosphorylation at C275 (P = 0.0364);.;.;.;
MVP		0.99
MPC		0.49
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.94

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: rs863224451; hg19: chr17-7577114; COSMIC: COSV52661919; COSMIC: COSV52661919;