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NM_000546.6(TP53):c.375+1dup AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jun 18, 2022
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:
RCV001021043.5

Allele description [Variation Report for NM_000546.6(TP53):c.375+1dup]

NM_000546.6(TP53):c.375+1dup

Gene:
TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000546.6(TP53):c.375+1dup
HGVS:
  • NC_000017.11:g.7675994dup
  • NG_017013.2:g.16558dup
  • NM_000546.6:c.375+1dupMANE SELECT
  • NM_001126112.3:c.375+1dup
  • NM_001126113.3:c.375+1dup
  • NM_001126114.3:c.375+1dup
  • NM_001126118.2:c.258+1dup
  • NM_001276695.3:c.258+1dup
  • NM_001276696.3:c.258+1dup
  • NM_001276760.3:c.258+1dup
  • NM_001276761.3:c.258+1dup
  • NM_001407262.1:c.375+1dup
  • NM_001407263.1:c.258+1dup
  • NM_001407264.1:c.375+1dup
  • NM_001407265.1:c.258+1dup
  • NM_001407266.1:c.375+1dup
  • NM_001407267.1:c.258+1dup
  • NM_001407268.1:c.375+1dup
  • NM_001407269.1:c.258+1dup
  • NM_001407270.1:c.375+1dup
  • NM_001407271.1:c.258+1dup
  • LRG_321:g.16558dup
  • NC_000017.10:g.7579310_7579311insC
  • NC_000017.10:g.7579312dup
  • NM_000546.4:c.375+1dupG
  • NM_000546.5:c.375+1dupG
Links:
dbSNP: rs1555526470
NCBI 1000 Genomes Browser:
rs1555526470
Molecular consequence:
  • NM_000546.6:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126112.3:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126113.3:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126114.3:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001126118.2:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276695.3:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276696.3:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276760.3:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001276761.3:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407262.1:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407263.1:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407264.1:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407265.1:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407266.1:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407267.1:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407268.1:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407269.1:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407270.1:c.375+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407271.1:c.258+1dup - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001182606Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Aug 29, 2019) 		germlineclinical testing

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

Citation Link,

SCV002582399Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jun 18, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families.

Manoukian S, Peissel B, Pensotti V, Barile M, Cortesi L, Stacchiotti S, Terenziani M, Barbera F, Pasquini G, Frigerio S, Pierotti MA, Radice P, Della-Torre G.

Eur J Cancer. 2007 Feb;43(3):601-6. Epub 2007 Jan 16.

PubMed [citation]
PMID:
17224268

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV001182606.4

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

Description

The c.375+1dupG intronic pathogenic mutation, results from the duplication of one nucleotide at nucleotide position 375 after intron 3 of the TP53 gene. This alteration was reported in an individual with breast cancer at 34 years of age who has a family member with sarcoma (Manoukian S et al. Eur. J. Cancer, 2007 Feb;43:601-6). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to shift the native donor site by one nucleotide leading to a frameshift. This prediction is supported by preliminary RNA evidence (Ambry internal data). Another alteration at this same splice donor site (c.375+1G>A) has been reported in a family with early-onset bilateral breast cancer, leukemia, and a CNS tumor as well as in a female patient diagnosed with adrenal cortical carcinoma at age 11 months (Frebourg T et al. Am J Hum Genet. 1995 Mar;56(3):608-15; Pinto EM et al. Nat Commun. 2015 Mar 6;6:6302). In addition to the data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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

From Genome-Nilou Lab, SCV002582399.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024