17-7673752-G-C

Variant names:

• chr17-7673752-G-C
• rs770374782
• NM_000546.6:c.868C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_000546.6(TP53):​c.868C>G​(p.Arg290Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R290C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.72
• Publications: 169 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 30 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-7673752-G-C is Benign according to our data. Variant chr17-7673752-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 628970.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.868C>G	p.Arg290Gly	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.868C>G	p.Arg290Gly	missense_variant	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Li-Fraumeni syndrome Uncertain:1

Feb 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 290 of the TP53 protein (p.Arg290Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 628970). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 15781620, 29979965, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.057
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.67	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	Uncertain	2.6	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PhyloP100		3.7
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.7	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.027	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Uncertain	0.023	D;D;D;T;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0010, 0.0040, 0.098	.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4		0.38
MutPred		0.47		Loss of stability (P = 0.0164);.;.;.;.;.;.;.;Loss of stability (P = 0.0164);.;Loss of stability (P = 0.0164);Loss of stability (P = 0.0164);Loss of stability (P = 0.0164);.;.;Loss of stability (P = 0.0164);.;.;.;
MVP		0.94
MPC		0.26
ClinPred		0.95	D
GERP RS		4.1
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.66
gMVP		0.30

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

Other links and lift over

dbSNP: rs770374782; hg19: chr17-7577070;