ClinVar Genomic variation as it relates to human health

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.

The p.I2179M variant (also known as c.6537T>G), located in coding exon 44 of the ATM gene, results from a T to G substitution at nucleotide position 6537. The isoleucine at codon 2179 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in a cohort of 3,579 African male prostate cancer cases and controls who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 methionine, which is neutral and non-polar, at codon 2179 of the ATM protein (p.Ile2179Met). This variant is present in population databases (rs146243469, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 35264596). ClinVar contains an entry for this variant (Variation ID: 186221). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

In silico analysis supports that this missense variant does not alter protein structure/function; Reported in a breast/prostate cancer case-control study, with no significant difference in frequency between cases and controls (p=0.28) (PMID: 23555315); Observed in individuals with a personal and/or family history of breast cancer, as well as an individual with pheochromocytoma/paraganglioma (PMID: 25186627, 31206626, 35264596, 35980532, 36568162, 37529773); This variant is associated with the following publications: (PMID: 28093192, 25186627, 32832836, 23532176, 31206626, 35264596, 35980532, 37529773, 23555315, 36568162)

The frequency of this variant in the general population, 0.00056 (14/24972 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 23555315 (2013), 25186627 (2015), and 35264596 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: ATM c.6537T>G (p.Ile2179Met) results in a conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 150980 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database (v3.1 genomes dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. However, the variant was also reported in the FLOSSIES database in 7/2559 African American women (i.e. with an allele frequency of 0.001367), who were older than age 70 years who have never had cancer, suggesting that the variant is likely benign. c.6537T>G has been reported in the literature, predominately as a VUS in settings of multigene panel testing, in individuals affected with Breast Cancer or other tumor phenotype(s), who are primarily of Hispanic- or African ancestry, without strong evidence for causality (e.g. Haiman_2013, Tung_2014, Weitzel_2019, Pereira_2022, van der Merwe_2022, Guindalini_2022, Lima_2023). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 35264596, 23555315, 35980532, 25186627, 31206626, 36568162, 37529773). ClinVar contains an entry for this variant (Variation ID: 186221). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The ATM c.6537T>G variant is predicted to result in the amino acid substitution p.Ile2179Met. This variant has been reported in an individual with breast cancer (Tung et al. 2015. PubMed ID: 25186627) and an individual with leiomyosarcoma (Lee et al. 2017. PubMed ID: 28093192). It was reported in a GWAS study of breast and prostate cancer risk in a multiethnic population (Haiman et al. 2013. PubMed ID: 23555315, Table S6.2). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the vast majority of laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186221/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.