ClinVar

Description

The ATM p.Ala799Val variant was identified in 1 of 16622 proband chromosomes (frequency: 0.00006) from individuals or families with Lynch syndrome or breast cancer and was present in 4 of 22482 control chromosomes (frequency: 0.0002) from healthy individuals (Momozawa 2018, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs199954262) as "With Uncertain significance allele", ClinVar (classified as likely benign by GeneDx and Ambry Genetics; and as uncertain significance by Invitae and two other submitters), LOVD 3.0 (2x), and in 7 of 277034 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 7 of 126620 chromosomes (freq: 0.00006), but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala799 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.