ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: ATM c.3517T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00022 in 277144 control chromosomes, predominantly at a frequency of 0.0023 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 2.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.3517T>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.1386delG), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as likely 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.

The ATM p.Leu1173= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs141460670) as "With other allele", ClinVar (classified as benign by GeneDx and Invitae; likely benign by Ambry Genetics, University of Chicago, Color Genomics and EGL Genetic Diagnostics), LOVD 3.0 (classified as likely benign by VKGL data sharing initiative).The variant was identified in control databases in 60 of 277144 chromosomes at a frequency of 0.0002 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: African in 56 of 24030 chromosomes (freq: 0.002), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 1 of 126642 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Leu1173= 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 and the nucleotide is not conserved in mammals. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant occurs 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 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.