ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The ATM p.Cys219= variant was identified in 1 of 404 proband chromosomes (frequency: 0.0024) from individuals or families with cancer, although the cancer type was unspecified (Petereit 2013). The variant was also identified in 4 of 186 control chromsomes (freq. 0.022) in unaffected individuals (Thorstenson 2001). The variant was also identified in dbSBP (ID: rs2235003) as “With other allele,” ClinVar (as likely benign by Genetics Services Laboratory University of Chicago and Illumina and as benign by Ambry Genetics, Invitae, Prevention Genetics, and Color Genomics), Clinvitae, and ATM-LOVD databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0 databases. The variant was identified in control databases in 2436 of 276942 chromosomes at a frequency of 0.008796 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the African population at a frequency greater than 1% in 2217 (101 homozygous) of 23994 chromosomes (freq: 0.092), and at lower frequencies in the following populations: Other in 22 of 6448 chromosomes (freq. 0.003), Latino in 166 (1 homozygous) of 34366 chromosomes (freq. 0.0048), and European (Non-Finnish) in 25 of 126568 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant. The p.Cys219Cys 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 this variant meets our laboratory's criteria to be classified as benign.

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.