17-7676148-G-C

Variant names:

• chr17-7676148-G-C
• NM_000546.6:c.221C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000546.6(TP53):​c.221C>G​(p.Ala74Gly) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.07

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13067889).
• BP6: Variant 17-7676148-G-C is Benign according to our data. Variant chr17-7676148-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1787901.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.221C>G	p.Ala74Gly	missense_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.221C>G	p.Ala74Gly	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Aug 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 1787901). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 74 of the TP53 protein (p.Ala74Gly). -

Hereditary cancer-predisposing syndrome Benign:1

Jun 19, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	3.0
DANN	Benign	0.50
DEOGEN2	Benign	0.018	T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.55	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.75	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;.;T;.;.;T;T;.;.;T;.;.;T;.;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.61	P;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.
Vest4		0.20
MutPred		0.27		Gain of catalytic residue at A74 (P = 0.0435);Gain of catalytic residue at A74 (P = 0.0435);.;Gain of catalytic residue at A74 (P = 0.0435);.;Gain of catalytic residue at A74 (P = 0.0435);Gain of catalytic residue at A74 (P = 0.0435);Gain of catalytic residue at A74 (P = 0.0435);.;.;Gain of catalytic residue at A74 (P = 0.0435);.;Gain of catalytic residue at A74 (P = 0.0435);Gain of catalytic residue at A74 (P = 0.0435);Gain of catalytic residue at A74 (P = 0.0435);Gain of catalytic residue at A74 (P = 0.0435);
MVP		0.82
MPC		0.65
ClinPred		0.19	T
GERP RS		-4.1
Varity_R		0.10
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7579466;