NM_007294.4(BRCA1):c.134+5G>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Sep 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001010944.2

Allele description [Variation Report for NM_007294.4(BRCA1):c.134+5G>A]

NM_007294.4(BRCA1):c.134+5G>A

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.4(BRCA1):c.134+5G>A
HGVS:
  • NC_000017.11:g.43115721C>T
  • NG_005905.2:g.102263G>A
  • NM_007294.4:c.134+5G>AMANE SELECT
  • NM_007297.4:c.-8+8296G>A
  • NM_007298.3:c.134+5G>A
  • NM_007299.4:c.134+5G>A
  • NM_007300.4:c.134+5G>A
  • LRG_292t1:c.134+5G>A
  • LRG_292:g.102263G>A
  • NC_000017.10:g.41267738C>T
  • NM_007294.3:c.134+5G>A
  • U14680.1:n.253+5G>A
Nucleotide change:
IVS3+5G>A
Links:
Breast Cancer Information Core (BIC) (BRCA1): 253+5&base_change=G to A; dbSNP: rs80358038
NCBI 1000 Genomes Browser:
rs80358038
Molecular consequence:
  • NM_007294.4:c.134+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007297.4:c.-8+8296G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007298.3:c.134+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.134+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007300.4:c.134+5G>A - intron variant - [Sequence Ontology: SO:0001627]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218] - Comment(s)
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001171209Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Sep 9, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

Baert A, Machackova E, Coene I, Cremin C, Turner K, Portigal-Todd C, Asrat MJ, Nuk J, Mindlin A, Young S, MacMillan A, Van Maerken T, Trbusek M, McKinnon W, Wood ME, Foulkes WD, Santamariña M, de la Hoya M, Foretova L, Poppe B, Vral A, Rosseel T, et al.

Hum Mutat. 2018 Apr;39(4):515-526. doi: 10.1002/humu.23390. Epub 2018 Jan 22.

PubMed [citation]
PMID:
29280214

Accurate classification of BRCA1 variants with saturation genome editing.

Findlay GM, Daza RM, Martin B, Zhang MD, Leith AP, Gasperini M, Janizek JD, Huang X, Starita LM, Shendure J.

Nature. 2018 Oct;562(7726):217-222. doi: 10.1038/s41586-018-0461-z. Epub 2018 Sep 12.

PubMed [citation]
PMID:
30209399
PMCID:
PMC6181777

Details of each submission

From Ambry Genetics, SCV001171209.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The c.134+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 2 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). One functional study found all substitutions at this nucleotide position are deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, a variant at the same nucleotide position, BRCA1 c.134+5G>T, causes skipping of of coding exon 2 (also called exon 3 in the literature: Baert A et al. Hum. Mutat., 2018 04;39:515-526). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: May 10, 2021

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