ClinVar

Description

The ATM c.1066-6T>G variant was identified in 51 of 18,694 proband chromosomes (frequency: 0.003) from individuals or families with chronic lymphocatic leukemia, breast or ovarian cancer and was present in 70 of 27,754 control chromosomes (frequency: 0.003) from healthy individuals (Ding 2010, Tiao 2017). The variant was identified in dbSNP (rs201686625) as “with other allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Integrated Genetics and 5 other submitters; as benign by Invitae, Color, Athena Diagnostics and 2 other submitters; and as likely benign by GeneDx and 2 other submitters) and LOVD 3.0 (observed 8x). The variant was identified in control databases in 357 of 266,346 chromosomes (2 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 23,658 chromosomes (freq: 0.0003), Other in 2 of 6198 chromosomes (freq: 0.0003), Latino in 19 of 32,652 chromosomes (freq: 0.0006), European in 286 of 123,010 chromosomes (freq: 0.002), Finnish in 18 of 25,254 chromosomes (freq: 0.0007), and South Asian in 25 of 27,738 chromosomes (freq: 0.0009); it was not observed in the Ashkenazi Jewish or East Asian populations. The variant was identified by our laboratory in multiple patients with pathogenic variants in BRCA2 (including c.1929del, p.Arg645Glufs*15 and c.755_758del, p.Asp252Valfs*24). The variant was also identified in the homozygous state in a patient with ataxia telangiectasia (Dork 2001), for whom alternate pathogenic variants were subsequently identified (Tavtigian 2009). A patient with mild ataxia telangiectasia was found to carry this variant in the compound heterozygous state and had reduced ATM protein expression and kinase activity, indicating this variant does not fully abolish protein expression and function (Austen 2016). Additionally, this variant leads to an increase in exon 11 skipping, although some exon 11 skipping is found in controls who do not carry this variant (Soukupova 2007). The c.1066-6T>G variant is located in the 3' splice region and does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence; variants involving these positions sometimes affect splicing and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.