ClinVar

Description

The ATM p.His674Arg variant was identified in the ATM mutation-screening data from the literature study in 1 of 4798 (freq. 0.0002) control chromosomes from healthy individuals and was not identified in 8224 proband chromosomes from individuals or families with breast cancer (Tavtigian 2009). The variant was also identified in dbSNP (ID: rs201762714) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and four other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 45 of 277138 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5 of 34418 chromosomes (freq: 0.0002), European in 14 of 126640 chromosomes (freq: 0.0001), and South Asian in 26 of 30782 chromosomes (freq: 0.0009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.His674 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.