NM_000546.6(TP53):c.1150A>G (p.Met384Val) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000213071.5

Allele description [Variation Report for NM_000546.6(TP53):c.1150A>G (p.Met384Val)]

NM_000546.6(TP53):c.1150A>G (p.Met384Val)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.1150A>G (p.Met384Val)

Other names:

p.M384V:ATG>GTG

HGVS:

NC_000017.11:g.7669641T>C
NG_017013.2:g.22910A>G
NM_000546.6:c.1150A>GMANE SELECT
NM_001126112.3:c.1150A>G
NM_001126113.3:c.*169A>G
NM_001126114.3:c.*257A>G
NM_001126115.2:c.754A>G
NM_001126116.2:c.*257A>G
NM_001126117.2:c.*169A>G
NM_001126118.2:c.1033A>G
NM_001276695.3:c.*169A>G
NM_001276696.3:c.*257A>G
NM_001276697.3:c.673A>G
NM_001276698.3:c.*257A>G
NM_001276699.3:c.*169A>G
NM_001276760.3:c.1033A>G
NM_001276761.3:c.1033A>G
NP_000537.3:p.Met384Val
NP_000537.3:p.Met384Val
NP_001119584.1:p.Met384Val
NP_001119587.1:p.Met252Val
NP_001119590.1:p.Met345Val
NP_001263626.1:p.Met225Val
NP_001263689.1:p.Met345Val
NP_001263690.1:p.Met345Val
LRG_321t1:c.1150A>G
LRG_321t2:c.1150A>G
LRG_321t6:c.*257A>G
LRG_321:g.22910A>G
LRG_321p1:p.Met384Val
NC_000017.10:g.7572959T>C
NM_000546.4:c.1150A>G
NM_000546.5:c.1150A>G
NM_001126112.2(TP53):c.1150A>G
NM_001126116.1:c.*257A>G
p.M384V
p.Met384Val

Protein change:

M225V

Links:

dbSNP: rs730882009

NCBI 1000 Genomes Browser:

rs730882009

Molecular consequence:

NM_001126113.3:c.*169A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126114.3:c.*257A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126116.2:c.*257A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126117.2:c.*169A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276695.3:c.*169A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276696.3:c.*257A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276698.3:c.*257A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276699.3:c.*169A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000546.6:c.1150A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.1150A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.1033A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.673A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.1033A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.1033A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211770	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Apr 3, 2017)	germline	clinical testing	Citation Link,
SCV000697427	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25980754, 25186627, 12826609 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211770

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Apr 3, 2017)

germline

clinical testing

Citation Link,

SCV000697427

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 31, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]

PMID:: 25980754
PMCID:: PMC4550537

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000211770.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697427.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 16, 2025

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