NM_000546.6(TP53):c.645T>A (p.Ser215Arg) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 26, 2023
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:: RCV002857438.4

Allele description [Variation Report for NM_000546.6(TP53):c.645T>A (p.Ser215Arg)]

NM_000546.6(TP53):c.645T>A (p.Ser215Arg)

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.645T>A (p.Ser215Arg)

HGVS:

NC_000017.11:g.7674886A>T
NG_017013.2:g.17665T>A
NM_000546.6:c.645T>AMANE SELECT
NM_001126112.3:c.645T>A
NM_001126113.3:c.645T>A
NM_001126114.3:c.645T>A
NM_001126115.2:c.249T>A
NM_001126116.2:c.249T>A
NM_001126117.2:c.249T>A
NM_001126118.2:c.528T>A
NM_001276695.3:c.528T>A
NM_001276696.3:c.528T>A
NM_001276697.3:c.168T>A
NM_001276698.3:c.168T>A
NM_001276699.3:c.168T>A
NM_001276760.3:c.528T>A
NM_001276761.3:c.528T>A
NM_001407262.1:c.645T>A
NM_001407263.1:c.528T>A
NM_001407264.1:c.645T>A
NM_001407265.1:c.528T>A
NM_001407266.1:c.645T>A
NM_001407267.1:c.528T>A
NM_001407268.1:c.645T>A
NM_001407269.1:c.528T>A
NM_001407270.1:c.645T>A
NM_001407271.1:c.528T>A
NP_000537.3:p.Ser215Arg
NP_000537.3:p.Ser215Arg
NP_001119584.1:p.Ser215Arg
NP_001119584.1:p.Ser215Arg
NP_001119585.1:p.Ser215Arg
NP_001119585.1:p.Ser215Arg
NP_001119586.1:p.Ser215Arg
NP_001119586.1:p.Ser215Arg
NP_001119587.1:p.Ser83Arg
NP_001119587.1:p.Ser83Arg
NP_001119588.1:p.Ser83Arg
NP_001119588.1:p.Ser83Arg
NP_001119589.1:p.Ser83Arg
NP_001119589.1:p.Ser83Arg
NP_001119590.1:p.Ser176Arg
NP_001119590.1:p.Ser176Arg
NP_001263624.1:p.Ser176Arg
NP_001263625.1:p.Ser176Arg
NP_001263626.1:p.Ser56Arg
NP_001263627.1:p.Ser56Arg
NP_001263628.1:p.Ser56Arg
NP_001263689.1:p.Ser176Arg
NP_001263690.1:p.Ser176Arg
NP_001394191.1:p.Ser215Arg
NP_001394192.1:p.Ser176Arg
NP_001394193.1:p.Ser215Arg
NP_001394194.1:p.Ser176Arg
NP_001394195.1:p.Ser215Arg
NP_001394196.1:p.Ser176Arg
NP_001394197.1:p.Ser215Arg
NP_001394198.1:p.Ser176Arg
NP_001394199.1:p.Ser215Arg
NP_001394200.1:p.Ser176Arg
LRG_321t1:c.645T>A
LRG_321t2:c.645T>A
LRG_321t3:c.645T>A
LRG_321t4:c.645T>A
LRG_321t5:c.249T>A
LRG_321t6:c.249T>A
LRG_321t7:c.249T>A
LRG_321t8:c.528T>A
LRG_321:g.17665T>A
LRG_321:p.Ser215Arg
LRG_321p1:p.Ser215Arg
LRG_321p3:p.Ser215Arg
LRG_321p4:p.Ser215Arg
LRG_321p5:p.Ser83Arg
LRG_321p6:p.Ser83Arg
LRG_321p7:p.Ser83Arg
LRG_321p8:p.Ser176Arg
NC_000017.10:g.7578204A>T
NM_000546.5:c.645T>A
NM_001126112.2:c.645T>A
NM_001126113.2:c.645T>A
NM_001126114.2:c.645T>A
NM_001126115.1:c.249T>A
NM_001126116.1:c.249T>A
NM_001126117.1:c.249T>A
NM_001126118.1:c.528T>A

Protein change:

S176R

Molecular consequence:

NM_000546.6:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.249T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.249T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.249T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.168T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.168T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.168T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407262.1:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407263.1:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407264.1:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407265.1:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407266.1:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407267.1:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407268.1:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407269.1:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407270.1:c.645T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407271.1:c.528T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003226212	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32817165, 28492532
SCV004829137	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003226212

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 30, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004829137

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 26, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome.

Gao F, Pan X, Dodd-Eaton EB, Recio CV, Montierth MD, Bojadzieva J, Mai PL, Zelley K, Johnson VE, Braun D, Nichols KE, Garber JE, Savage SA, Strong LC, Wang W.

Genome Res. 2020 Aug;30(8):1170-1180. doi: 10.1101/gr.249599.119. Epub 2020 Aug 18.

PubMed [citation]

PMID:: 32817165
PMCID:: PMC7462073

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003226212.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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 of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 32817165). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 215 of the TP53 protein (p.Ser215Arg).

#	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

From All of Us Research Program, National Institutes of Health, SCV004829137.1

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

Description

This missense variant replaces serine with arginine at codon 215 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TP53-related disorders in the literature. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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