NM_007294.4(BRCA1):c.2861dup (p.Ser955fs) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 25, 2019)

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:
RCV000779904.3

Allele description [Variation Report for NM_007294.4(BRCA1):c.2861dup (p.Ser955fs)]

NM_007294.4(BRCA1):c.2861dup (p.Ser955fs)

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.2861dup (p.Ser955fs)
Other names:
2980dupT
HGVS:
  • NC_000017.11:g.43092670dup
  • NG_005905.2:g.125314dup
  • NM_007294.4:c.2861dupMANE SELECT
  • NM_007297.4:c.2720dup
  • NM_007298.3:c.788-1638dup
  • NM_007299.4:c.788-1638dup
  • NM_007300.4:c.2861dup
  • NP_009225.1:p.Ser955fs
  • NP_009228.2:p.Ser908fs
  • NP_009231.2:p.Ser955fs
  • LRG_292:g.125314dup
  • NC_000017.10:g.41244686_41244687insA
  • NC_000017.10:g.41244687dup
  • NM_007294.3:c.2861dupT
  • NM_007294.4:c.2861dupTMANE SELECT
  • NR_027676.2:n.3038dup
  • p.Ser955fs
Protein change:
S908fs
Links:
dbSNP: rs886040079
NCBI 1000 Genomes Browser:
rs886040079
Molecular consequence:
  • NM_007294.4:c.2861dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007297.4:c.2720dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007300.4:c.2861dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007298.3:c.788-1638dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.788-1638dup - intron variant - [Sequence Ontology: SO:0001627]
  • NR_027676.2:n.3038dup - 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
SCV000916806Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Sep 25, 2018)
germlineclinical testing

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

Citation Link,

SCV001401115Invitaecriteria provided, single submitter
Pathogenic
(Jul 25, 2019)
germlineclinical testing

PubMed (3)
[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

Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study.

Azzollini J, Scuvera G, Bruno E, Pasanisi P, Zaffaroni D, Calvello M, Pasini B, Ripamonti CB, Colombo M, Pensotti V, Radice P, Peissel B, Manoukian S.

Eur J Intern Med. 2016 Jul;32:65-71. doi: 10.1016/j.ejim.2016.03.010. Epub 2016 Apr 6.

PubMed [citation]
PMID:
27062684

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]
PMID:
20104584
PMCID:
PMC2928257
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916806.1

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

Description

Variant summary: BRCA1 c.2861dupT (p.Ser955IlefsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2864C>A, p.Ser955X; c.2868delT, p.Gln957fsX43; c.2901_2902dupTC, p.Pro968fsX33). The variant was absent in 246124 control chromosomes (gnomAD). The variant, c.2861dupT, has been reported in the literature in one family affected with Hereditary Breast and Ovarian Cancer (Azzollini_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Invitae, SCV001401115.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ser955Ilefs*16) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with personal and/or family history of breast and/or ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 266311). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). 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: Sep 23, 2021

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