FANCA S1088F - GET-Evidence

Curation:
Currentness:

FANCA S1088F

(FANCA Ser1088Phe)


Short summary

Probably benign. One report hypothesized this variant causing Fanconi Anemia, but the allele frequency (3-7%) is high enough to contradict a highly penetrant pathogenic effect. Later authors have concluded this is a polymorphism, not pathogenic.

Variant evidence
Computational -1

Gene is associated with the disease and Polyphen 2 predicts damaging effect (0.905)

Functional -
Case/Control 3

Findings in controls contradict pathogenic effect, and allele frequency is inconsistent with the rarity of the disease.

See Wijker M et al. 1999 (10094191), Seal S et al. 2003 (14695169), unpublished research (below).

Familial 1
 
Clinical importance
Severity
Treatability
Penetrance

published hypothesis implies high penetrance

 

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

Out of 64 genomes from Complete Genomics, one (GS20502) is homozygous for this variant — this is added here as controls. The combined data has no statistical significance.

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
Fanconi Anemia
- - 1 63 - -

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Fanconi Anemia
1 35 1 113 0.4236 3.229

 

Allele frequency

  • A @ chr16:89815152: 5.8% (629/10758) in EVS
  • A @ chr16:88342652: 7.0% (9/128) in GET-Evidence
  • Frequency shown in summary reports: 5.8% (629/10758)

Publications
 

Wijker M, Morgan NV, Herterich S, van Berkel CG, Tipping AJ, Gross HJ, Gille JJ, Pals G, Savino M, Altay C, Mohan S, Dokal I, Cavenagh J, Marsh J, van Weel M, Ortega JJ, Schuler D, Samochatova E, Karwacki M, Bekassy AN, Abecasis M, Ebell W, Kwee ML, de Ravel T, CG Mathew, et al. Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene. Eur J Hum Genet. 1999 Jan;7(1):52-9. PubMed PMID: 10094191.

In a screen of 36 patients with Fanconi Anemia, this variant was seen homozygously in an Iranian individual with consanguineous parents. The variant was not seen in 100 controls chromosomes. Using two-tailed Fisher’s exact: p=0.17

Cases/controls case+ case– control+ control– p-value odds ratio
Fanconi Anemia
1 35 0 50 0.4186

 

Seal S, Barfoot R, Jayatilake H, Smith P, Renwick A, Bascombe L, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N; Breast Cancer Susceptibility Collaboration. Evaluation of Fanconi Anemia genes in familial breast cancer predisposition. Cancer Res. 2003 Dec 15;63(24):8596-9. PubMed PMID: 14695169.

These authors found that this variant is relatively common in controls (although they don’t give the exact numbers) and conclude it is a polymorphism, not causal.

Genomes
 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het A @ chr16:89815152

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr16:89815152

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het A @ chr16:89815152

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het A @ chr16:89815152

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr16:89815152

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het A @ chr16:89815152

 

GS06985 - var-GS06985-1100-36-ASM
het A @ chr16:88342653

 

GS18947 - var-GS18947-1100-36-ASM
het A @ chr16:88342653

 

GS19649 - var-GS19649-1100-36-ASM
het A @ chr16:88342653

 

GS20502 - var-GS20502-1100-36-ASM
hom A @ chr16:88342653

 

Other external references
 

    dbSNP
  • rs17233497
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    Web search results (10 hits -- see all)
  • Evaluation of Fanconi Anemia Genes in Familial Breast Cancer ...
    FANCA L1143V was identified in family B637, which consists of twin ... FANCA S1088F was reported as the causative mutation in a consanguineous Middle Eastern FA-A family (19) ...
    cancerres.aacrjournals.org/cgi/content/full/63/24/8596
  • FANCA Mutations
    FANCA. PolyMut. polymorphism. Mutation. 2151G>T. Published Name. G2195T ... S1088F. Exon. exon 33. Type. AA substitution. Comment. Changed from mutation to polymorphism 12 ...
    www.rockefeller.edu/fanconi/mutate/public/faapoly_pub.html
  • Type I- 99%
    ... belgian patient PRB2 P02812 S274P 274 VAR_019695 CK1 (0.632) Con1-, abolishes the glycosylation site at ... 693) possible polymorphism FANCA O15360 S1088F 1088 VAR_017501 CAMKL ...
    www.nih.go.kr/phosphovariant/html/family_whole/TypeI-_99.txt
  • Type I- 97%
    ... CK1 (0.632) Con1-, abolishes the glycosylation site at position 238 8554050 NME1 ... P05177 S18C 18 VAR_023196 PKC (0.816) 15469410 15643613 FANCA O15360 S1088F 1088 ...
    www.nih.go.kr/phosphovariant/html/family_whole/TypeI-_97.txt

Other in silico analyses
 

  • NBLOSUM100 score = 5
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in