Submissions for variant NM_000051.4(ATM):c.7559T>C (p.Met2520Thr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325295	SCV004031235	uncertain significance	Ataxia-telangiectasia syndrome	2023-07-21	criteria provided, single submitter	clinical testing	The ATM c.7559T>C (p.Met2520Thr) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was not reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia or breast cancer. Please note that a different nucleotide substitution impacting the same position: c.7559T>G (p.Met2520Arg) has been reported in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142749/) as pathogenic or likely pathogenic based on in-silico and/or RNA-studies due to introducing dinucleotide AG and subsequent activation of cryptic acceptor splice site. However, the current substitution in this sample c.7559T>C (p.Met2520Thr) is not predicted to introduce dinucleotide AG/cryptic acceptor splice site. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.