LIG4 A3V - GET-Evidence

Curation:
Currentness:

LIG4 A3V

(LIG4 Ala3Val)


Short summary

One report has associated this with a decreased risk of multiple myeloma.

Variant evidence
Computational -1

Polyphen 2 predicts no functional effect.

Functional -
Case/Control 1

p = 0.025, but authors did not correct for multiple hypotheses.

See Roddam PL et al. 2002 (12471202).

Familial -
 
Clinical importance
Severity 4
Treatability 2
Penetrance 1

Multiple myeloma is very rare, accounting for roughly 1% of all cancers, and so the decreased lifetime risk is between 0.1% and 0.5%.

 

Impact

Low clinical importance, Uncertain protective

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

Inheritance pattern

dominant

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr13:108863609: 3.6% (378/10546) in EVS
  • A @ chr13:107661609: 4.7% (6/128) in GET-Evidence
  • Frequency shown in summary reports: 3.6% (378/10546)

Publications
 

Roddam PL, Rollinson S, O'Driscoll M, Jeggo PA, Jack A, Morgan GJ. Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination. J Med Genet. 2002 Dec;39(12):900-5. PubMed PMID: 12471202; PubMed Central PMCID: PMC1757220.

Investigating how variants in this gene, DNA ligase IV (involved in double-stranded break repair in antigen gene rearrangement mechanisms — which are thought to be involved in lymphoproliferative disorders), these authors found that A3V and T9I variants have a protective association with multiple myeloma. They also examined adult acute lymphoblastoma cases and lymphoma cases, in which they found no significant correlations.

Among the multiple myeloma cases, case A/A: 247, A/V: 20, V/V: 1, and in controls A/A: 189, A/V: 31, V/V: 0. Counting carriers, this is case+: 21, case-: 247, control+: 31, control-: 189. Using a two-tailed Fisher’s Exact test this is p = 0.0277.

The authors report a “significant interaction (p < 0.05)” using the chi-squared test, but do not mention correcting for multiple hypotheses — at least three different disease hypotheses and two variants were being tested here, and so this correction would imply the required p-value should be more like 0.025 (for 2 hypotheses) to 0.008 (for 6 hypotheses). Based on this, we treat this variant as having an effective p-value between 0.1 and 0.05.

Genomes
 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr13:108863609

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het A @ chr13:108863609

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
hom A @ chr13:108863609

 

GS18526 - var-GS18526-1100-36-ASM
het A @ chr13:107661610

 

Other external references
 

    dbSNP
  • rs1805389
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.004 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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