NM_007294.4(BRCA1):c.4997dup (p.Tyr1666Ter) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 21, 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:
RCV000499541.5

Allele description [Variation Report for NM_007294.4(BRCA1):c.4997dup (p.Tyr1666Ter)]

NM_007294.4(BRCA1):c.4997dup (p.Tyr1666Ter)

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.4997dup (p.Tyr1666Ter)
Other names:
p.Y1666X:TAC>TAA
HGVS:
  • NC_000017.11:g.43067685dup
  • NG_005905.2:g.150299dup
  • NM_007294.3:c.4997dup
  • NM_007294.4:c.4997dupMANE SELECT
  • NM_007297.4:c.4856dup
  • NM_007298.3:c.1685dup
  • NM_007299.4:c.1685dup
  • NM_007300.4:c.5060dup
  • NP_009225.1:p.Tyr1666Ter
  • NP_009225.1:p.Tyr1666Ter
  • NP_009228.2:p.Tyr1619Ter
  • NP_009229.2:p.Tyr562Ter
  • NP_009230.2:p.Tyr562Ter
  • NP_009231.2:p.Tyr1687Ter
  • LRG_292t1:c.4997dup
  • LRG_292:g.150299dup
  • LRG_292p1:p.Tyr1666Ter
  • NC_000017.10:g.41219701_41219702insT
  • NC_000017.10:g.41219702dup
  • NM_007294.3:c.4997dupA
  • NR_027676.2:n.5174dup
  • p.(Tyr1666Ter)
  • p.Tyr1666*
Protein change:
Y1619*
Links:
dbSNP: rs876658947
NCBI 1000 Genomes Browser:
rs876658947
Molecular consequence:
  • NR_027676.2:n.5174dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_007294.3:c.4997dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007294.4:c.4997dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007297.4:c.4856dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007298.3:c.1685dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007299.4:c.1685dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007300.4:c.5060dup - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000918718Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Oct 5, 2017)
germlineclinical testing

Citation Link,

SCV001223548Invitaecriteria provided, single submitter
Pathogenic
(Nov 21, 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 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

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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918718.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: The BRCA1 c.4997dupA (p.Tyr1666X) variant involves the duplication of an adenine nucleotide resulting in a premature stop codon. Truncating variants downstream of the variant of interest have been assessed as pathogenic by our laboratory (e.g., c.5289delG [p.Leu1764fsX1] and c.5335delC [p.Gln1779fsX14]). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 246126 control chromosomes. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.

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

From Invitae, SCV001223548.2

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

Description

This sequence change creates a premature translational stop signal (p.Tyr1666*) 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 not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 231083). 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: Jun 14, 2021

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