NM_000546.6(TP53):c.919+1G>A AND Li-Fraumeni syndrome

Clinical significance:Likely pathogenic (Last evaluated: Aug 28, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000991150.3

Allele description [Variation Report for NM_000546.6(TP53):c.919+1G>A]

NM_000546.6(TP53):c.919+1G>A

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.919+1G>A
Other names:
NM_001276761.1:c.802+1G>A
HGVS:
  • NC_000017.11:g.7673700C>T
  • NG_017013.2:g.18851G>A
  • NM_000546.5:c.919+1G>A
  • NM_000546.6:c.919+1G>AMANE SELECT
  • NM_001126112.2:c.919+1G>A
  • NM_001126113.2:c.919+1G>A
  • NM_001126114.2:c.919+1G>A
  • NM_001126115.1:c.523+1G>A
  • NM_001126116.1:c.523+1G>A
  • NM_001126117.1:c.523+1G>A
  • NM_001126118.1:c.802+1G>A
  • NM_001276695.2:c.802+1G>A
  • NM_001276696.2:c.802+1G>A
  • NM_001276697.2:c.442+1G>A
  • NM_001276698.2:c.442+1G>A
  • NM_001276699.2:c.442+1G>A
  • NM_001276760.2:c.802+1G>A
  • NM_001276761.2:c.802+1G>A
  • LRG_321t1:c.919+1G>A
  • LRG_321t2:c.919+1G>A
  • LRG_321t3:c.919+1G>A
  • LRG_321t4:c.919+1G>A
  • LRG_321t5:c.523+1G>A
  • LRG_321t6:c.523+1G>A
  • LRG_321t7:c.523+1G>A
  • LRG_321t8:c.802+1G>A
  • LRG_321:g.18851G>A
  • NC_000017.10:g.7577018C>T
Links:
dbSNP: rs1131691039
NCBI 1000 Genomes Browser:
rs1131691039
Molecular consequence:
  • NM_000546.5:c.919+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126112.2:c.919+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126113.2:c.919+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126114.2:c.919+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126115.1:c.523+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126116.1:c.523+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126117.1:c.523+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126118.1:c.802+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276695.2:c.802+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276696.2:c.802+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276697.2:c.442+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276698.2:c.442+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276699.2:c.442+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276760.2:c.802+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276761.2:c.802+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Functional consequence:
sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071] - Comment(s)

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
SCV001142564ClinGen TP53 Variant Curation Expert Panel,ClinGenreviewed by expert panel
Likely pathogenic
(Aug 28, 2019)
germlinecuration

Citation Link,

SCV001382474Invitaecriteria provided, single submitter
Pathogenic
(Oct 9, 2020)
germlineclinical testing

PubMed (6)
[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

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome.

Renaux-Petel M, Charbonnier F, Théry JC, Fermey P, Lienard G, Bou J, Coutant S, Vezain M, Kasper E, Fourneaux S, Manase S, Blanluet M, Leheup B, Mansuy L, Champigneulle J, Chappé C, Longy M, Sévenet N, Paillerets BB, Guerrini-Rousseau L, Brugières L, Caron O, et al.

J Med Genet. 2018 Mar;55(3):173-180. doi: 10.1136/jmedgenet-2017-104976. Epub 2017 Oct 25.

PubMed [citation]
PMID:
29070607

Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark.

Stoltze U, Skytte AB, Roed H, Hasle H, Ejlertsen B, Overeem Hansen TV, Schmiegelow K, Gerdes AM, Wadt K.

PLoS One. 2018;13(1):e0190050. doi: 10.1371/journal.pone.0190050.

PubMed [citation]
PMID:
29324801
PMCID:
PMC5764253
See all PubMed Citations (6)

Details of each submission

From ClinGen TP53 Variant Curation Expert Panel,ClinGen, SCV001142564.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.919+1G>A is canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is a proband with a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (PM6_Supporting; PMID: 28509937). In summary, TP53 c.919+1G>A meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PM6_Supporting.

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

From Invitae, SCV001382474.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change affects a donor splice site in intron 8 of the TP53 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals with Li-Fraumeni syndrome (PMID: 29070607, 29324801, 20805372). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 633606). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Aug 27, 2021

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