ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 11505391, 27599564)

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.

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

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.

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.

The ATM p.Pro1526= variant was identified in 520 of 9784 proband chromosomes (frequency: 0.05) from individuals or families with unselected multiple myeloma, breast cancer and was identified in 395 of 6700 control chromosomes (frequency: 0.059) from healthy individuals (Austen 2008, Concannon 2008, Petereit 2013, Stredrick 2006, Tommiska 2006). The variant was also identified in dbSNP (ID: rs rs1800889) as “other”, ClinVar (classified as benign by Invitae, Ambry Genetics, Prevention Genetics, Color Genomics; classified as likely benign by Illumina, GSLUOC), Cosmic (classified as neutral), LOVD 3.0 (does not affect function), databases. The variant was not identified in GeneInsight-COGR, MutDB, ATM-LOVD, databases. The variant was identified in control databases in 9064 (227 homozygous) of 277100 chromosomes at a frequency of 0.03 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 6425 of 126614 chromosomes (freq: 0.051), Other in 212 of 6458 chromosomes (freq: 0.033), Latino in 1062 of 34414 chromosomes (freq: 0.031), European (Finnish) in 641 of 25788 chromosomes (freq: 0.025), Ashkenazi Jewish* in 131 of 10146 chromosomes (freq: 0.013), South Asian in 396 of 30782 chromosomes (freq: 0.013). The p.Pro1526Pro 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 outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, few studies suggest the variant not associated with breast cancer risk and classify the variant as SNP (Stredrick 2006, Tommiska 2006). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.