NM_000546.6(TP53):c.641A>G (p.His214Arg) AND Li-Fraumeni syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 15, 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:: RCV004022220.3

Allele description [Variation Report for NM_000546.6(TP53):c.641A>G (p.His214Arg)]

NM_000546.6(TP53):c.641A>G (p.His214Arg)

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.641A>G (p.His214Arg)

HGVS:

NC_000017.11:g.7674890T>C
NG_017013.2:g.17661A>G
NM_000546.6:c.641A>GMANE SELECT
NM_001126112.3:c.641A>G
NM_001126113.3:c.641A>G
NM_001126114.3:c.641A>G
NM_001126115.2:c.245A>G
NM_001126116.2:c.245A>G
NM_001126117.2:c.245A>G
NM_001126118.2:c.524A>G
NM_001276695.3:c.524A>G
NM_001276696.3:c.524A>G
NM_001276697.3:c.164A>G
NM_001276698.3:c.164A>G
NM_001276699.3:c.164A>G
NM_001276760.3:c.524A>G
NM_001276761.3:c.524A>G
NP_000537.3:p.His214Arg
NP_000537.3:p.His214Arg
NP_001119584.1:p.His214Arg
NP_001119585.1:p.His214Arg
NP_001119586.1:p.His214Arg
NP_001119587.1:p.His82Arg
NP_001119588.1:p.His82Arg
NP_001119589.1:p.His82Arg
NP_001119590.1:p.His175Arg
NP_001263624.1:p.His175Arg
NP_001263625.1:p.His175Arg
NP_001263626.1:p.His55Arg
NP_001263627.1:p.His55Arg
NP_001263628.1:p.His55Arg
NP_001263689.1:p.His175Arg
NP_001263690.1:p.His175Arg
LRG_321t1:c.641A>G
LRG_321:g.17661A>G
LRG_321p1:p.His214Arg
NC_000017.10:g.7578208T>C
NM_000546.4:c.641A>G
NM_000546.5(TP53):c.641A>G
NM_000546.5:c.641A>G
p.His214Arg

Protein change:

H175R

Links:

dbSNP: rs1057519992

NCBI 1000 Genomes Browser:

rs1057519992

Molecular consequence:

NM_000546.6:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.641A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.245A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.245A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.245A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Li-Fraumeni syndrome 1 (LFS)
Identifiers:: Gene: 553989; MedGen: C1835398; Orphanet: 524; OMIM: 151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004932854	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Feb 15, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005088415	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 36168441, 31881331, 31533767, 29070607, 27050224, 24810334, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004932854

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Feb 15, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV005088415

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 15, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013..

PubMed [citation]

PMID:: 29979965

A case report: invasive ductal carcinoma in mosaic Li-Fraumeni syndrome.

Wenger D, Kurumety S, Aydi ZB.

J Surg Case Rep. 2022 Sep;2022(9):rjac408. doi: 10.1093/jscr/rjac408.

PubMed [citation]

PMID:: 36168441
PMCID:: PMC9509207

See all PubMed Citations (8)

Details of each submission

From Myriad Genetics, Inc., SCV004932854.1

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

Description

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV005088415.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (7)

Description

A heterozygous missense variant in exon 6 of the TP53 gene (chr17:g.7674890T>C; Depth: 180x) that results in the amino acid substitution of Arginine for Histidine at codon 214 (p.His214Arg; ENST00000269305.9) was detected. The p.His214Arg variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico predictions of the variant are probably damaging by PolyPhen-2 and damging by SIFT, LRT, Mutation Taster2 tools. The reference codon is conserved in species. The Alternate allele depth of this TP53 variant is low [16.1%]. This could be due to germline mosaicism which has been reported for TP53 variants.

#	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		1	not provided	not provided	not provided

Last Updated: May 25, 2025

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