NM_007294.4(BRCA1):c.301+1G>C AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Uncertain significance (Last evaluated: Dec 4, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000705646.2

Allele description [Variation Report for NM_007294.4(BRCA1):c.301+1G>C]

NM_007294.4(BRCA1):c.301+1G>C

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.301+1G>C
HGVS:
  • NC_000017.11:g.43104867C>G
  • NG_005905.2:g.113117G>C
  • NM_007294.4:c.301+1G>CMANE SELECT
  • NM_007297.4:c.160+1G>C
  • NM_007298.3:c.301+1G>C
  • NM_007299.4:c.301+1G>C
  • NM_007300.4:c.301+1G>C
  • LRG_292t1:c.301+1G>C
  • LRG_292:g.113117G>C
  • NC_000017.10:g.41256884C>G
  • NM_007294.3:c.301+1G>C
Links:
dbSNP: rs587782173
NCBI 1000 Genomes Browser:
rs587782173
Molecular consequence:
  • NM_007294.4:c.301+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_007297.4:c.160+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_007298.3:c.301+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_007299.4:c.301+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_007300.4:c.301+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218] - Comment(s)

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000834653Invitaecriteria provided, single submitter
Uncertain significance
(Dec 4, 2019)
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

Citations

PubMed

Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members.

Thomassen M, Blanco A, Montagna M, Hansen TV, Pedersen IS, Gutiérrez-Enríquez S, Menéndez M, Fachal L, Santamariña M, Steffensen AY, Jønson L, Agata S, Whiley P, Tognazzo S, Tornero E, Jensen UB, Balmaña J, Kruse TA, Goldgar DE, Lázaro C, Diez O, Spurdle AB, et al.

Breast Cancer Res Treat. 2012 Apr;132(3):1009-23. doi: 10.1007/s10549-011-1674-0. Epub 2011 Jul 19.

PubMed [citation]
PMID:
21769658

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000834653.3

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

Description

This sequence change affects a donor splice site in intron 5 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587782173, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 267517). An experimental study has shown that a different variant (c.301+6T>C) affecting a nucleotide within the consensus splice site of the intron results in an aberrant transcript encoding an in-frame deletion of 3 amino acids at the exon 5-6 junction (referred to as the exon 6-7 junction) (PMID: 21769658). While the effect of this variant (c.301+1G>C) has not been assessed experimentally, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant disrupts the consensus splice site and creates a cryptic donor splice site 9 nucleotides upstream, leading to the in-frame loss of 3 amino acids. This is similarly predicted and experimentally demonstrated for c.301+6T>C. These data suggest that an upstream, cryptic donor site can potentially rescue disruption of the canonical donor site, thereby preserving the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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