NM_007294.4(BRCA1):c.5154G>T (p.Trp1718Cys) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Feb 27, 2021)

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:
RCV001328383.2

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)

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
SCV001519505Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
Pathogenic
(Feb 27, 2021)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001576506Invitaecriteria provided, single submitter
Likely pathogenic
(Feb 6, 2020)
germlineclinical testing

PubMed (10)
[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

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, et al.

J Clin Oncol. 2015 Feb 1;33(4):304-11. doi: 10.1200/JCO.2014.57.1414. Epub 2014 Dec 1.

PubMed [citation]
PMID:
25452441
PMCID:
PMC4302212

Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.

LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC.

PLoS One. 2017;12(2):e0170843. doi: 10.1371/journal.pone.0170843.

PubMed [citation]
PMID:
28152038
PMCID:
PMC5289469
See all PubMed Citations (14)

Details of each submission

From Integrated Genetics/Laboratory Corporation of America, SCV001519505.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant summary: BRCA1 c.5154G>T (p.Trp1718Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250912 control chromosomes. c.5154G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and to co-segregate with disease in at-least one multigenerational family with early onset breast cancer (example, Mirkovic_2004, LaDuca_2017, Blay_2013, Momozawa_2018). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of activity in multiple independent assays to include homology directed repair (HDR) capacity, protein folding stability, binding specificity to known functional target of the BRCA1 BRCT domain and transcriptional activity (example, Findlay_2018, Lee_2010). 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 likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Invitae, SCV001576506.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change replaces tryptophan with cysteine at codon 1718 of the BRCA1 protein (p.Trp1718Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with breast cancer in a family (PMID: 15172985), and has been observed in several individuals affected with hereditary breast and ovarian cancer (PMID: 12491487, 23683081, 26153499). ClinVar contains an entry for this variant (Variation ID: 55435). This variant has been reported to affect BRCA1 protein function (PMID: 15172985, 16528612, 20516115, 23867111, 14534301, 30209399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: May 14, 2021

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