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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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001481785ClinGen TP53 Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen TP53 ACMG Specifications TP53 V2.0.0)
Likely Pathogenic
(Sep 6, 2024)
germlinecuration

Citation Link,

SCV001557553Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 14, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot 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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 16, 2025