17-7669641-T-C

Variant names:

• chr17-7669641-T-C
• rs730882009
• NM_000546.6:c.1150A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. BP4 PM2_Supporting BS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.1150A>G variant in TP53 is a missense variant predicted to cause substitution of methionine by valine at amino acid 384 (p.Met384Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: Invitae). Computational predictor scores (BayesDel = -0.073; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). This variant has an allele frequency of 0.00001780 (21/1179926 alleles) in the Europen (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 2.0; 1/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000046/MONDO:0018875/009

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:7 B:2
• Conservation: PhyloP100: 0.379
• Publications: 14 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: Likely_benign. The variant received -4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.1150A>G	p.Met384Val	missense	Exon 11 of 11	NP_000537.3
	TP53	NM_001126112.3		c.1150A>G	p.Met384Val	missense	Exon 11 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.1150A>G	p.Met384Val	missense	Exon 12 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.1150A>G	p.Met384Val	missense	Exon 11 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.1150A>G	p.Met384Val	missense	Exon 11 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.1033A>G	p.Met345Val	missense	Exon 10 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

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: 20 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111896

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2 Benign:1

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Jan 16, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.1150A>G variant in TP53 is a missense variant predicted to cause substitution of methionine by valine at amino acid 384 (p.Met384Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: Invitae). Computational predictor scores (BayesDel = -0.073; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). This variant has an allele frequency of 0.00001780 (21/1179926 alleles) in the Europen (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 2.0; 1/16/2025).

not specified Uncertain:2

Apr 03, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 31, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.1150A>G (p.Met384Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1150A>G has been reported in the literature in an individual with Breast cancer (Tung_2014) and another individual suspected with Lynch syndrome (Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, and reportes the variant as partially inactive (Kato_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12826609, 25186627, 25980754). ClinVar contains an entry for this variant (Variation ID: 182939). Based on the evidence outlined above, the variant was classified as uncertain significance.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Dec 12, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 06, 2025

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.

not provided Uncertain:1

Dec 18, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TP53 c.1150A>G (p.Met384Val) variant has been reported in the published literature in individuals with breast cancer (PMID: 25186627 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)) and in an individual with suspected Lynch syndrome (PMID: 25980754 (2015)). Published functional studies on this variant show a partial loss of TP53 activity in a yeast-based assay (PMID: 12826609 (2003)) and did not show a loss-of-function effect in human cell lines (PMID: 30224644 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

TP53-related disorder Uncertain:1

Nov 30, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Benign	0.63
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.38
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.10	T
Polyphen		0.033	B
Vest4		0.33
MutPred		0.40		Gain of sheet (P = 0.0827)
MVP		0.91
MPC		1.7
ClinPred		0.090	T
GERP RS		1.5
Varity_R		0.28
gMVP		0.29
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs730882009; hg19: chr17-7572959;