NM_000546.6(TP53):c.482_487del (p.Ala161_Tyr163delinsAsp) AND Li-Fraumeni syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 6, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001361575.10

Allele description [Variation Report for NM_000546.6(TP53):c.482_487del (p.Ala161_Tyr163delinsAsp)]

NM_000546.6(TP53):c.482_487del (p.Ala161_Tyr163delinsAsp)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.482_487del (p.Ala161_Tyr163delinsAsp)

HGVS:

NC_000017.11:g.7675125_7675130del
NG_017013.2:g.17421_17426del
NM_000546.6:c.482_487delMANE SELECT
NM_001126112.3:c.482_487del
NM_001126113.3:c.482_487del
NM_001126114.3:c.482_487del
NM_001126115.2:c.86_91del
NM_001126116.2:c.86_91del
NM_001126117.2:c.86_91del
NM_001126118.2:c.365_370del
NM_001276695.3:c.365_370del
NM_001276696.3:c.365_370del
NM_001276697.3:c.5_10del
NM_001276698.3:c.5_10del
NM_001276699.3:c.5_10del
NM_001276760.3:c.365_370del
NM_001276761.3:c.365_370del
NP_000537.3:p.Ala161_Tyr163delinsAsp
NP_001119584.1:p.Ala161_Tyr163delinsAsp
NP_001119585.1:p.Ala161_Tyr163delinsAsp
NP_001119586.1:p.Ala161_Tyr163delinsAsp
NP_001119587.1:p.Ala29_Tyr31delinsAsp
NP_001119588.1:p.Ala29_Tyr31delinsAsp
NP_001119589.1:p.Ala29_Tyr31delinsAsp
NP_001119590.1:p.Ala122_Tyr124delinsAsp
NP_001263624.1:p.Ala122_Tyr124delinsAsp
NP_001263625.1:p.Ala122_Tyr124delinsAsp
NP_001263626.1:p.Ala2_Tyr4delinsAsp
NP_001263627.1:p.Ala2_Tyr4delinsAsp
NP_001263628.1:p.Ala2_Tyr4delinsAsp
NP_001263689.1:p.Ala122_Tyr124delinsAsp
NP_001263690.1:p.Ala122_Tyr124delinsAsp
NP_001263690.1:p.Ala122_Tyr124delinsAsp
LRG_321t1:c.482_487del
LRG_321:g.17421_17426del
NC_000017.10:g.7578443_7578448del
NM_000546.5:c.482_487del
NM_001276761.2:c.365_370del

Links:

dbSNP: rs2073376974

NCBI 1000 Genomes Browser:

rs2073376974

Molecular consequence:

NM_000546.6:c.482_487del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126112.3:c.482_487del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126113.3:c.482_487del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126114.3:c.482_487del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126115.2:c.86_91del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126116.2:c.86_91del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126117.2:c.86_91del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001126118.2:c.365_370del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276695.3:c.365_370del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276696.3:c.365_370del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276697.3:c.5_10del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276698.3:c.5_10del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276699.3:c.5_10del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276760.3:c.365_370del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001276761.3:c.365_370del - inframe_indel - [Sequence Ontology: SO:0001820]

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
SCV001481785	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0)	Likely Pathogenic (Sep 6, 2024)	germline	curation	Citation Link,
SCV001557553	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29456621, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001481785

ClinGen TP53 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen TP53 ACMG Specifications TP53 V2.0.0)

Likely Pathogenic
(Sep 6, 2024)

germline

curation

Citation Link,

SCV001557553

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 14, 2023)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Men seeking counselling in a Breast Cancer Risk Evaluation Clinic.

Freitas AC, Opinião A, Fragoso S, Nunes H, Santos M, Clara A, Bento S, Luis A, Silva J, Moura C, Filipe B, Machado P, Santos S, André S, Rodrigues P, Parreira J, Vaz F.

Ecancermedicalscience. 2018;12:804. doi: 10.3332/ecancer.2018.804.

PubMed [citation]

PMID:: 29456621
PMCID:: PMC5813915

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

Details of each submission

From ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001481785.3

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

Description

The NM_000546.6:c.482_487del variant is predicted to cause a change in the length of the protein (p.Ala161_Tyr163delinsAsp) due to an in-frame deletion of 3 amino acids and insertion of 1 amino acid. This variant has been reported in 1 family meeting Classic Li-Fraumeni syndrome criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The individual missense variants, A161D and Y163D, used as proxies for this indel variant have 7 and 3 somatic occurrences, respectively, for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Another missense variant (c.488A>G, p.Tyr163Cys) (ClinVar Variation ID: 127814), in an involved codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP1, PM2_Supporting, PM1_Supporting, PM5. (Bayesian Points: 6; VCEP specifications version 2.0; 9/6/2024)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001557553.4

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TP53 protein in which other variant(s) (p.Ala161Thr) have been determined to be pathogenic (PMID: 29456621; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 973858). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.482_487del, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the TP53 protein (p.Ala161_Tyr163delinsAsp).

#	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: May 16, 2025

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