ClinVar

Description

Variant summary: ATM c.7187C>G (p.Thr2396Ser) results in a conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 256616 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00021 vs 0.001), allowing no conclusion about variant significance. In addition, the variant was also reported in 3/7325 European American women (i.e. with a frequency of 0.00041), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.7187C>G has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with a variety of cancers (example, breast, ovarian, melanoma, CLL, Lynch syndrome) with limited information (e.g. Paglia 2010, Tung_2015, Tavera-Tapia 2017, Goldstein 2017, Tiao 2017, Hauke 2018, Bonache_2018, Tsaousis_2019, Ferrer-Avargues_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature as we all as observed at our laboratory (our lab, BRCA1 c.3400G>T, p.Glu1134* ; Ferrer-Avargues_2021, MSH6 c.2079dup, p.Cys694MetfsTer), providing supporting evidence for a benign role. To our knowledge, no concrete experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=2, VUS, n=7). At-least one of these submitters has re-classified this variant to likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.