ClinVar

Description

The ATM p.Leu1420Phe variant was identified in 81 of 4298 proband chromosomes (frequency: 0.02) from English, French, Dutch, American Indian/Non-Indian, Australian and North American individuals or families with familial and primary breast cancers, AT disease, CML, and individuals undergoing radiation therapy and was present in 108 of 6302 control chromosomes (frequency: 0.02) from healthy individuals (Johnson 2007 , LaPaglia 2010, Broeks 2008, Melo 2001, Petereit 2013, Renwick 2006, Li 2000, Thompson 2005, ). In 2 population-based, case-control studies, the variant was found not to increase breast cancer risk (Einarsdottir 2006, Thompson 2005). The variant was also identified in dbSNP (ID: rs1800058) as “other”, ClinVar (classified as conflicting interpretations of pathogenicity: classified benign by GeneDx, Div of Genomic Diagnostics, Children's Hospital of Philadelphia, Vantari Genetics, Prevention Genetics, Emory Genetics, Color Genomics Inc., Invitae; likely benign by Genetic Services Laboratory, U of Chicago; uncertain significance by Ambry Genetics; and unclassified by ITMI), Clinvitae (5X), LOVD 3.0 (2X), ATM-LOVD (1x). The variant was not identified in GeneInsight-COGR, Cosmic and MutDB. The variant was identified in control databases in 3069 (22 homozygous) of 272226 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 2316 of 124884 chromosomes (freq: 0.019), European (Finnish) in 279 of 25640 chromosomes (freq: 0.011), Other in 67 of 6316 chromosomes (freq: 0.011). The p.Leu1420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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, this variant meets our laboratory's criteria to be classified as benign.