| 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. |
| Submitter | scavalieri@gmail.com |
| References | MedGen (Hereditary Cancer Predisposing Syndromes); PMID 12362033 |
