Free Mutation: ATM gene, c.4388T>G (p.Phe1463Cys)

Submission date 3 Oct 2016
Gene ATM
Mutation (gDNA level) chr11-108160480-T-G
Mutation (cDNA level) c.4388T>G
Reference sequence NM_000051.3
Prediction at protein level F1463C (p.Phe1463Cys)
Mutation type missense
Exon/intron location exon 29 of 63
Amino acid location aa 1463 of 3057
Gene associated phenotype(s) Ataxia-telangiectasia; Breast cancer, susceptibility to
ClinVar ID 127388
dbSNP ID rs138327406
Clinical information (terms) breast cancer
Clinical information (codes) HP:0003002
Sex female
A priori interpretation (Ataxia-telangiectasia) possibly not affecting function
A priori interpretation (Breast cancer, susceptibility to) uncertain significance
Comments This variant is currently reported in ClinVar with conflicting interpretations on pathogenicity based on multiple submissions. The variant  has an allele frequency ranging from 0.0004 (1000 Genomes) to 0.0014 (ExAC), with three homozygous individuals reported (ExAC). One ClinVar submission reports the variant to be benign in relation to ataxia-telangectasia. In relation to hereditary cancer predisposing syndrome, the variant has been reported in ClinVar once as benign and once as of uncertain significance. One additional ClinVar publication from 2002 on breast cancer classifies this variant as pathogenic. The nucleotoide and the amino acid positions are conserved. Some in silico algorithms indicate that the variant might be damaging (Mutation Taster, SIFT, Polyphen-2 and FATHMM-MKL), whereas some indicate that the variant might be neutral (SNP&GO, MetaSVM, MetalR and FATHMM). Based on the ExAC data and on current ClinVar entries, there is a possibility that the variant is not impacting the protein function in a way to cause ataxia-teleangectasia. In relation to susceptibility to breast cancer, based on current literature, the variant should be considered at least of uncertain significance.
References MedGen (Hereditary Cancer Predisposing Syndromes); PMID 12362033


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