ClinVar

Description

The ATM p.Thr935= variant was identified in 4 of 5562 proband chromosomes (frequency: 0.001) from individuals or families with contralateral breast cancer, breast carcinoma or chronic lymphocytic leukemia (Bernstein 2010, Mangone 2015, Skowronska 2012, Teraoka 2001). The variant was also identified in dbSNP (ID: rs55934812) as "With Likely benign, Uncertain significance allele", ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Ambry Genetics, Color Genomics; as uncertain significance by Integrated Genetics/Laboratory Corporation of America), and in LOVD 3.0 (1x as likely benign). The variant was not identified in COGR, and Cosmic databases. The variant was identified in control databases in 81 of 277128 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24032 chromosomes (freq: 0.0001), Other in 5 of 6464 chromosomes (freq: 0.001), Latino in 14 of 34420 chromosomes (freq: 0.0004), and European in 60 of 126690 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr935= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.