ClinVar

Description

The ATM p.Thr935Met variant was identified in 4 of 32596 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer, colorectal cancer or Lynch syndrome and was present in 1 of 11718 control chromosomes (frequency: 0.0001) from healthy individuals (Decker 2017, Pearlman 2017, Renwick 2006, Yurgelun 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs3218708) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Color; and as uncertain significance by Invitae, Counsyl, GeneDx and one other submitter). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 15 of 277146 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), European in 13 of 126690 chromosomes (freq: 0.0001), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Thr935 residue is not conserved in mammals and four out of five 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.