ClinVar

Description

Variant summary: ATM c.1695A>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: four predict the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by published functional studies. The variant allele was found at a frequency of 8e-06 in 251276 control chromosomes (gnomAD v2.1), including two carriers who were above age 75 year and were also part of the non-cancer datasets (gnomAD v2.1 and v3.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1695A>G in individuals affected with Ataxia-Telangiectasia (or other ATM-related phenotypes) and no experimental evidence demonstrating its impact on mRNA have been reported. ClinVar contains an entry for this variant (Variation ID: 407723), and one of the ClinVar submitters reported abnormal splicing in the set of samples tested (Ambry internal data), however these results were not available for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.