17-7676148-G-C

Position:

chr17-7676148-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The ENST00000269305.9(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A74V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.07

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:

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ACMG classification

Classification made for transcript

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: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.221C>G	p.Ala74Gly	missense_variant	4/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.221C>G	p.Ala74Gly	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2023

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 has not been reported in the literature in individuals affected with TP53-related conditions. 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2020

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

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

LIST_S2

Benign

0.55

T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.13

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.41

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over