NM_007294.4(BRCA1):c.5427dup (p.Val1810fs) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 15, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000504023.1

Allele description [Variation Report for NM_007294.4(BRCA1):c.5427dup (p.Val1810fs)]

NM_007294.4(BRCA1):c.5427dup (p.Val1810fs)

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.4(BRCA1):c.5427dup (p.Val1810fs)
HGVS:
  • NC_000017.11:g.43047684dup
  • NG_005905.2:g.170301dup
  • NM_007294.4:c.5427dupMANE SELECT
  • NM_007297.4:c.5286dup
  • NM_007298.3:c.2115dup
  • NM_007299.4:c.2041dup
  • NM_007300.4:c.5490dup
  • NP_009225.1:p.Val1810fs
  • NP_009228.2:p.Val1763fs
  • NP_009229.2:p.Val706fs
  • NP_009230.2:p.Cys681fs
  • NP_009231.2:p.Val1831fs
  • LRG_292:g.170301dup
  • NC_000017.10:g.41199701dup
  • NM_007294.3:c.5427dupT
  • NR_027676.2:n.5604dup
  • p.(Val1810CysfsTer20)
Protein change:
C681fs
Links:
dbSNP: rs1555574739
NCBI 1000 Genomes Browser:
rs1555574739
Molecular consequence:
  • NM_007294.4:c.5427dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007297.4:c.5286dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007298.3:c.2115dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007299.4:c.2041dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007300.4:c.5490dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_027676.2:n.5604dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000591631Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)criteria provided, single submitter
Likely pathogenic
(Jun 27, 2014)
germlineclinical testing

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

SCV000758804Invitaecriteria provided, single submitter
Pathogenic
(Nov 15, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

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

Functional variant analyses (FVAs) predict pathogenicity in the BRCA1 DNA double-strand break repair pathway.

Loke J, Pearlman A, Upadhyay K, Tesfa L, Shao Y, Ostrer H.

Hum Mol Genet. 2015 Jun 1;24(11):3030-7. doi: 10.1093/hmg/ddv048. Epub 2015 Feb 4.

PubMed [citation]
PMID:
25652403
See all PubMed Citations (6)

Details of each submission

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591631.1

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

From Invitae, SCV000758804.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Val1810Cysfs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acids of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 433737). This variant is expected to disrupt a portion of the C-terminal region of the BRCA1 protein containing the BRCT domain (residues Val1646-Pro1859) (PMID: 25652403). Although functional studies have not been performed for this particular variant, the BRCT domain is critical for BRCA1 DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). This suggests that disruption of this region of the BRCA1 protein is causative of disease. 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: Apr 18, 2021

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