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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This variant is associated with the following publications: (PMID: 12810666)

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.

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

ATM: BP4, BP7, BS1, BS2

The ATM p.Val245= variant was identified in 44 of 3228 proband chromosomes (frequency: 0.01) from individuals or families with b-cell lymphoma tumours, chronic lymphocytic leukemia and hereditary breast and ovarian cancer and was present in 74 of 4368 control chromosomes (frequency: 0.007) from healthy individuals (Skowronska 2012, Concannon 2008, Gronbaek 2002, Heikkinen 2005, Mangone 2015, Petereit 2013, Tommiska 2006). The variant was identified in dbSNP (rs3218674) as “with likely benign, other allele, ClinVar (classified as benign by Invitae, Ambry Genetics, Color, PreventionGenetics and 2 other submitters and likely benign by True Health Diagnostics, Illumina and Counsyl) and LOVD 3.0 (observed 5x). The variant was identified in control databases in 3269 of 282,410 chromosomes (43 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 1057 of 25,098 chromosomes (freq: 0.04), European in 1977 of 128,822 chromosomes (freq: 0.02), Other in 78 of 7206 chromosomes (freq: 0.01), Latino in 100 of 35,408 chromosomes (freq: 0.003), African in 45 of 24,960 chromosomes (freq: 0.002), South Asian in 10 of 30,610 chromosomes (freq: 0.0003), Ahkenazi Jewish in 2 of 10,360 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian population. The p.Val245= 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. The variant occurs at a non-highly conserved nucleotide 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 this variant meets our laboratory's criteria to be classified as benign.