ClinVar Genomic variation as it relates to human health

Variant summary: ATM c.78A>T (p.Glu26Asp) results in a conservative amino acid change located in the telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251078 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.78A>T has been reported in the literature in at least one individual affected with Prostate Cancer (e.g. Karlsson_2021). This report does not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with prostate cancer (PMID: 33436325); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28779002, 33436325)

This missense variant replaces glutamic acid with aspartic acid at codon 26 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 3/282468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The ATM c.78A>T; p.Glu26Asp variant (rs786202953) is reported in an individual with prostate cancer (Karlsson 2021). This variant is also reported in ClinVar (Variation ID: 186439). It is observed in the general population with an overall allele frequency of 0.001% (3/282468 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.16). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Karlsson Q et al. Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. Eur Urol Oncol. 2021 Aug;4(4):570-579. PMID: 33436325.

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 26 of the ATM protein (p.Glu26Asp). This variant is present in population databases (rs786202953, gnomAD 0.002%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 186439). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.E26D variant (also known as c.78A>T), located in coding exon 2 of the ATM gene, results from an A to T substitution at nucleotide position 78. The glutamic acid at codon 26 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 Nov;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.