BRCA1 Q356R - GET-Evidence

Curation:
Currentness:

BRCA1 Q356R

(BRCA1 Gln356Arg)


Short summary

One common variant associated this variant with an increased risk of breast cancer, but a more recent, larger study found no association.

Variant evidence
Computational -1

Gene Associated with disease, Polyphen 2 predicts damaging effect

Functional -
Case/Control

Results of Johnson et al. contradicted by Dombernowsky et al.

See Johnson N et al. 2007 (17341484), Dombernowsky SL et al. 2009 (19661094).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -

Attributable increased risk of 6%, see below

See Johnson N et al. 2007 (17341484).

 

Impact

Low clinical importance, Uncertain benign

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

undefined

Summary of published research, and additional commentary

 

Total cases/controls case+ case– control+ control– p-value odds ratio
BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
79 393 257 2203 0.0002 1.723

 

Allele frequency

  • C @ chr17:41246481: 4.6% (498/10758) in EVS
  • C @ chr17:38500006: 2.3% (3/128) in GET-Evidence
  • Frequency shown in summary reports: 4.6% (498/10758)

Publications
 

Johnson N, Fletcher O, Palles C, Rudd M, Webb E, Sellick G, dos Santos Silva I, McCormack V, Gibson L, Fraser A, Leonard A, Gilham C, Tavtigian SV, Ashworth A, Houlston R, Peto J. Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet. 2007 May 1;16(9):1051-7. Epub 2007 Mar 6. PubMed PMID: 17341484.

Patients were evaluated who had a history of at least two primary primary breast cancers (bilateral or asynchronous ipsilateral), with the first diagnosis made before the age of 65. Of these, 4 were homozygous for this variant, 75 were heterozygous, and 393 did not have it. In the controls there were 7 homozygous, 250 heterozygous, and 2203 not carrying the variant.

Testing this with the PGP calculator and assuming a lifetime risk of breast cancer of 12%, the PGP calculator estimates that carriers have an attributable increased risk of ~6% (total risk of ~18%).

Cases/controls case+ case– control+ control– p-value odds ratio
BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
79 393 257 2203 0.0002 1.723

 

Dombernowsky SL, Weischer M, Freiberg JJ, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2009 Aug;18(8):2339-42. PubMed PMID: 19661094.

These authors report finding no association between this variant and the risk of breast or ovarian cancer. Notably this study was much larger than Johnson et al., with a 39-year prospective study of 5,743 women, and a case-control with 1,201 cases and 4,120 controls.

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr17:41246481

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het C @ chr17:41246481

 

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het C @ chr17:41246481

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het C @ chr17:41246481

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
hom C @ chr17:41246481

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het C @ chr17:41246481

 

Other external references
 

    dbSNP
  • rs1799950
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the BRCA1 gene
    BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
    BRCA1 Hereditary Breast/Ovarian Cancer
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/BRCA1
    PolyPhen-2
  • Score: 0.996 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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