ClinVar Genomic variation as it relates to human health

This variant is denoted ATM c.275A>C at the cDNA level, p.Lys92Thr (K92T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ATM Lys92Thr was observed at an allele frequency of 0.11% (19/18,844) in individuals of East Asian ancestry in large population cohorts (Lek 2016). ATM Lys92Thr is located in region of interaction with p53 & BRCA1 (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Lys92Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant summary: The c.275A>C (p.Lys92Thr) in ATM gene is a missense variant involves a conserved nucleotide and 3/4 in silico tools predict deleterious outcome. Although, the variant is located within the TAN motif that is essential for both telomere length maintenance and Tel1 action in response to DNA damage, no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. In addition, based on the conservation alignment, the change could be tolerated. The variant is present in the control population datasets of ExAC and gnomAD (7.657e-05; 9/117540 and 0.000068; 19/276920 chrs tested, respectively), exclusively in individuals of East Asian descent (0.0010). The individual frequencies are similar to the maximal expected allele frequency for a disease causing allele in ATM gene (0.001), suggesting that this variant may represent a rare ethnic polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited by several reputable databases/clinical laboratories as VUS. Taken together, the variant was classified as VUS-Possibly Benign, until new information becomes available.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.