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NM_007294.3(BRCA1):c.4675G>A (p.Glu1559Lys) AND not provided

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 28, 2015
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000482921.1

Allele description

NM_007294.3(BRCA1):c.4675G>A (p.Glu1559Lys)

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.3(BRCA1):c.4675G>A (p.Glu1559Lys)
HGVS:
  • NC_000017.11:g.43074331C>T
  • NG_005905.2:g.143653G>A
  • NM_007294.3:c.4675G>A
  • NM_007297.4:c.4534G>A
  • NM_007298.3:c.1363G>A
  • NM_007299.4:c.1363G>A
  • NM_007300.4:c.4738G>A
  • NP_009225.1:p.Glu1559Lys
  • NP_009228.2:p.Glu1512Lys
  • NP_009229.2:p.Glu455Lys
  • NP_009230.2:p.Glu455Lys
  • NP_009231.2:p.Glu1580Lys
  • LRG_292t1:c.4675G>A
  • LRG_292:g.143653G>A
  • LRG_292p1:p.Glu1559Lys
  • NC_000017.10:g.41226348C>T
  • NR_027676.1:n.4811G>A
  • U14680.1:n.4794G>A
  • p.E1559K
Nucleotide change:
4794G>A
Protein change:
E1512K
Links:
dbSNP: rs80356988
NCBI 1000 Genomes Browser:
rs80356988
Molecular consequence:
  • NM_007294.3:c.4675G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.4534G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.1363G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.1363G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.4738G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000564744GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))
Likely pathogenic
(Feb 28, 2015)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000564744.3

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

Description

This variant is denoted BRCA1 c.4675G>A at the cDNA level. Using alternate nomenclature, this variant has been previously published as BRCA1 4794G>A. Located in last nucleotide of exon 14, multiple splicing models predict that this variant destroys the natural splice donor site for intron 14 and causes abnormal splicing. BRCA1 c.4675G>A has been reported in at least three individuals with ovarian cancer (Wappenschmidt 2012, Janavicius 2014, Tihomirova 2014). In addition, RNA analysis suggested that this variant results in partial loss of the natural splice donor site and activation of a cryptic splice donor site (Wappenschmidt 2012). Although the nucleotide substitution results in the change of a Glutamic Acid to a Lysine at codon 1559, and is called Glu1559Lys in the literature, we are using only the nucleotide nomenclature to refer to the mutation since the defect is mainly due to abnormal splicing rather than a resulting missense pathogenic variant. BRCA1 c.4675G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The nucleotide which is altered, a guanine (G) at base 4675, is conserved across species. Based on the current evidence, we consider this mutation to be a likely pathogenic variant.

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

Last Updated: Dec 16, 2019