BRCA2 N372H - GET-Evidence

Curation:
Currentness:

BRCA2 N372H

(BRCA2 Asn372His)


Short summary

This is a common variant of BRCA2 (HapMap allele frequency of 23%). The variant is weakly associated with an increased chance of breast cancer, and zygosity of the variant is associated with sex of children: male children are more likely to be homozygous for this variant, female children are more likely to be heterozygous.

Variant evidence
Computational

Gene is associated with breast cancer, but polyphen predicts benign effect

Functional -
Case/Control 2

p = 0.026

See Healey CS et al. 2000 (11062481).

Familial
 
Clinical importance
Severity 4

Breast cancer is potentially lethal

Treatability 3

Screening and treatment may reduce mortality

Penetrance 2

2% attributable risk

See Healey CS et al. 2000 (11062481).

 

Impact

Low clinical importance, Uncertain pathogenic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • C @ chr13:32906729: 23.7% (2517/10640) in EVS
  • C @ chr13:31804728: 23.4% (30/128) in GET-Evidence
  • Frequency shown in summary reports: 23.7% (2517/10640)

Publications
 

Healey CS, Dunning AM, Teare MD, Chase D, Parker L, Burn J, Chang-Claude J, Mannermaa A, Kataja V, Huntsman DG, Pharoah PD, Luben RN, Easton DF, Ponder BA. A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Nat Genet. 2000 Nov;26(3):362-4. PubMed PMID: 11062481.

Combining five case-control studies (three British, one German, one Finnish) they find that homozygousity for this variant is associated with increased breast cancer risk with OR=1.3, p=0.026. They estimate that the population attributable risk of breast cancer due to N372H is ~2% (0.48-3.34 95% confidence).

Deviation from Hardy-Weinberg equilibrium (the expected distribution of heterozygotes and homozygotes) caused them to investigate and find that there is a reduced rate of homozygous females (0.82 fitness relative to heterozygous) and an increased rate of heterozygous. Testing newborns they conclude that this difference is occurring prior to birth — females have an excess of heterozygotes and deficit of homozygotes (p=0.06), males have an excess of homozygotes and a deficit of heterozygotes (p=0.001).

Teare MD, Cox A, Shorto J, Anderson C, Bishop DT, Cannings C. Heterozygote excess is repeatedly observed in females at the BRCA2 locus N372H. J Med Genet. 2004 Jul;41(7):523-8. PubMed PMID: 15235023; PubMed Central PMCID: PMC1735827.

 

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr13:32906729

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het C @ chr13:32906729

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het C @ chr13:32906729

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr13:32906729

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het C @ chr13:32906729

 

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het C @ chr13:32906729

 

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
hom C @ chr13:32906729

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het C @ chr13:32906729

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het C @ chr13:32906729

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom C @ chr13:32906729

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het C @ chr13:32906729

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het C @ chr13:32906729

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het C @ chr13:32906729

 

GS06985 - var-GS06985-1100-36-ASM
het C @ chr13:31804729

 

GS07357 - var-GS07357-1100-36-ASM
het C @ chr13:31804729

 

GS12004 - var-GS12004-1100-36-ASM
het C @ chr13:31804729

 

GS18504 - var-GS18504-1100-36-ASM
het C @ chr13:31804729

 

GS18526 - var-GS18526-1100-36-ASM
het C @ chr13:31804729

 

GS18558 - var-GS18558-1100-36-ASM
het C @ chr13:31804729

 

GS18956 - var-GS18956-1100-36-ASM
het C @ chr13:31804729

 

GS19020 - var-GS19020-1100-36-ASM
het C @ chr13:31804729

 

GS19129 - var-GS19129-1100-36-ASM
het C @ chr13:31804729

 

GS19700 - var-GS19700-1100-36-ASM
het C @ chr13:31804729

 

GS19703 - var-GS19703-1100-36-ASM
het C @ chr13:31804729

 

GS19735 - var-GS19735-1100-36-ASM
het C @ chr13:31804729

 

GS20502 - var-GS20502-1100-36-ASM
het C @ chr13:31804729

 

GS20509 - var-GS20509-1100-36-ASM
het C @ chr13:31804729

 

GS21767 - var-GS21767-1100-36-ASM
het C @ chr13:31804729

 

NA12878

 

Other external references
 

    dbSNP
  • rs144848
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the BRCA2 gene
    Prostate cancer
    Fanconi Anemia
    BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
    BRCA2 Hereditary Breast/Ovarian Cancer
    BRCA2-Related Fanconi Anemia
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/BRCA2

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in