17-7669641-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_000546.6(TP53):c.1150A>G(p.Met384Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M384T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:7B:1

Conservation

PhyloP100: 0.379

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14763045).

BP6

Variant 17-7669641-T-C is Benign according to our data. Variant chr17-7669641-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 182939.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.1150A>G	p.Met384Val	missense_variant	11/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.1150A>G	p.Met384Val	missense_variant	11/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727190

show subpopulations

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 384 of the TP53 protein (p.Met384Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 182939). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces methionine with valine at codon 384 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant has a partial impact on function in yeast transactivation assays (IARC database; PMID: 12826609) and did not impact function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 33471991) or suspected Lynch Syndrome (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 12, 2022	This missense variant replaces methionine with valine at codon 384 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant has a partial impact on function in yeast transactivation assays (IARC database; PMID: 12826609) and did not impact function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 33471991) or suspected Lynch Syndrome (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 24, 2023	The p.M384V variant (also known as c.1150A>G), located in coding exon 10 of the TP53 gene, results from an A to G substitution at nucleotide position 1150. The methionine at codon 384 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in patients affected with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant showed partially reduced transactivation capacity in comparison to wild type in a yeast-based functional assay (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2017

This variant is denoted TP53 c.1150A>G at the cDNA level, p.Met384Val (M384V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TP53 Met384Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Met384Val occurs at a position that is moderately conserved across species and is located in the basic (repression of DNA-binding) region, which is also a region responsible for interaction with Coactivator-Associated Arginine Methyltransferase 1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Met384Val is pathogenic or benign. We consider it to be a variant of uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 28, 2016

Variant summary: The TP53 c.1150A>G (p.Met384Val) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121408 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

TP53-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2022

The TP53 c.1150A>G variant is predicted to result in the amino acid substitution p.Met384Val. The TP53 gene variant c.1150A>G is predicted to result in the amino acid substitution p.Met384Val. This variant was identified in an individual suspected of having Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant has not been observed in the gnomAD database, indicating this variant is rare. It has been reported in ClinVar multiple times as a variant of uncertain significance however by ClinGen expert panel is this variant assessed as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/182939/). Transactivation assays show partial function of this variant (Kato et al. 2002. PubMed ID: 12826609) and there is no evidence of a dominant negative effect or loss of function (Giacomelli et al. 2018. PubMed ID: 30224644). In summary, we interpret this variant as uncertain. -

Li-Fraumeni syndrome 1

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Apr 12, 2021

This variant is absent from the gnomAD non-cancer v2.1.1 dataset (PM2_supporting). Transactivation assays show partial function according to Kato, et al (PMID: 12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli et al. (PMID: 30224644) (BS3_supporting). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.1150A>G; p.Met384Val meets criteria to be classified as Likely Benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting; BS3_supporting, BP4, BS2_supporting. In this case, PM2_Supporting is not applied to final classification as there is sufficient evidence for codes to meet Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

Cadd

Benign

Dann

Benign

0.63

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.84

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

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.15

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

MetaSVM

Uncertain

0.74

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.33

Sift4G

Benign

0.10

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

Polyphen

0.033

.;.;.;B;.;B;.;.

Vest4

0.33

MutPred

0.40

.;.;.;Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);.;.;

MVP

0.91

MPC

1.7

ClinPred

0.090

GERP RS

1.5

Varity_R

0.28

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over