NM_007294.4(BRCA1):c.5154G>T (p.Trp1718Cys) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Oct 25, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000482189.1

Allele description [Variation Report for NM_007294.4(BRCA1):c.5154G>T (p.Trp1718Cys)]

NM_007294.4(BRCA1):c.5154G>T (p.Trp1718Cys)

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.5154G>T (p.Trp1718Cys)
HGVS:
  • NC_000017.11:g.43063372C>A
  • NG_005905.2:g.154612G>T
  • NM_007294.3:c.5154G>T
  • NM_007294.4:c.5154G>TMANE SELECT
  • NM_007297.4:c.5013G>T
  • NM_007298.3:c.1842G>T
  • NM_007299.4:c.1842G>T
  • NM_007300.4:c.5217G>T
  • NP_009225.1:p.Trp1718Cys
  • NP_009225.1:p.Trp1718Cys
  • NP_009228.2:p.Trp1671Cys
  • NP_009229.2:p.Trp614Cys
  • NP_009230.2:p.Trp614Cys
  • NP_009231.2:p.Trp1739Cys
  • LRG_292t1:c.5154G>T
  • LRG_292:g.154612G>T
  • LRG_292p1:p.Trp1718Cys
  • NC_000017.10:g.41215389C>A
  • NR_027676.2:n.5331G>T
  • P38398:p.Trp1718Cys
  • U14680.1:n.5273G>T
  • p.W1718C
Protein change:
W1671C
Links:
UniProtKB: P38398#VAR_070503; dbSNP: rs80357239
NCBI 1000 Genomes Browser:
rs80357239
Molecular consequence:
  • NM_007294.3:c.5154G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007294.4:c.5154G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.5013G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007298.3:c.1842G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007299.4:c.1842G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.5217G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.5331G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218] - Comment(s)

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000572126GeneDxcriteria provided, single submitter
Likely pathogenic
(Oct 25, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Details of each submission

From GeneDx, SCV000572126.4

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

Description

This variant is denoted BRCA1 c.5154G>T at the cDNA level, p.Trp1718Cys (W1718C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). Using alternate nomenclature, this variant would be defined as/ has been previously published as BRCA1 5273G>T. This variant has been observed in individuals with triple negative breast cancer and familial breast/ovarian cancer, and was reported to segregate with disease in a breast cancer kindred (Blay 2013, Eccles 2015, Couch 2015). Functional assays have found this variant to impact transcriptional activation and lead to protein destabilization (Williams 2003, Mirkovic 2004, Lee 2010). Additionally, this variant demonstrated cisplatin sensitivity and lack of growth rescue similar to pathogenic variants in mouse embryonic stem cells (Bouwman 2013).BRCA1 Trp1718Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Trp1718Cys occurs at a position that is conserved in mammals and is located in the first BRCT domain and a region known to interact with multiple other proteins (UniProt, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA1 Trp1718Cys to be a likely pathogenic variant.

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

Last Updated: Jun 14, 2021

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