ClinVar Genomic variation as it relates to human health

This missense variant replaces isoleucine with valine at codon 2076 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. This variant has been reported in individuals affected with breast and colorectal cancer (PMID: 25186627, 28135145, 34299313). This variant has been identified in 3/251394 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.

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23532176, 28135145, 16832357, 34299313)

Variant summary: ATM c.6226A>G (p.Ile2076Val) results in a conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6226A>G has been reported in the literature in individuals taking multiple-gene panel testing for Colorectal Cancer or unspecified contion involving DNA repair pathways, without strong evidence for causality (example, Yurgelun_2017, Guglielmi_2021). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 1/60466 cases, not in 53461 controls (Dorling_2021 through LOVD).These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 34299313, 28135145). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.I2076V variant (also known as c.6226A>G), located in coding exon 42 of the ATM gene, results from an A to G substitution at nucleotide position 6226. The isoleucine at codon 2076 is replaced by valine, an amino acid with highly similar properties. In a large study of familial breast cancer families, this variant was identified in 1/443 cases and 0/521 controls (Renwick A et al. Nat. Genet., 2006 Aug;38:873-5). This alteration was also identified in an individual diagnosed with breast cancer (Guglielmi C et al. Int J Mol Sci, 2021 Jul;22:). This amino acid position is not 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.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2076 of the ATM protein (p.Ile2076Val). This variant is present in population databases (rs755973863, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 234090). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 ATM c.6226A>G variant is predicted to result in the amino acid substitution p.Ile2076Val. This variant was reported in individuals with colorectal cancer or breast cancer (Yurgelun et al. 2017. PubMed ID: 28135145; Tung N et al. 2014. PubMed ID: 25186627; Guglielmi C et al. 2021. PubMed ID: 34299313). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as a variant of uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/234090/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.