ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1982 of the ATM protein (p.Gln1982Arg). This variant is present in population databases (rs543980602, gnomAD 0.05%). This missense change has been observed in individual(s) with a personal or family history of breast or ovarian cancer and/or unspecified cancer (PMID: 25151137, 32068069). ClinVar contains an entry for this variant (Variation ID: 141800). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 missense variant replaces glutamine with arginine at codon 1982 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 cancer (PMID: cases: 12935933, 32068069, 33471991), and in unaffected controls (PMID: 19781682, 33471991). This variant has also been identified in 10/251190 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.

Variant summary: ATM c.5945A>G (p.Gln1982Arg) results in a conservative amino acid change located in the PIK-related kinase (IPR014009) 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 4e-05 in 251190 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.5945A>G has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with breast and/or ovarian cancers (example, Guan_2015, Kwong_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. 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: 25151137, 32068069). ClinVar contains an entry for this variant (Variation ID: 141800). Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in individuals with breast or ovarian cancer and also in unaffected controls (PMID: 19781682, 33471991, 32068069, 28569743, 32091409); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28256603, 12935933, 28569743, 32091409, 32068069, 33471991, 19781682, 23532176, 25151137)

The p.Q1982R variant (also known as c.5945A>G), located in coding exon 39 of the ATM gene, results from an A to G substitution at nucleotide position 5945. The glutamine at codon 1982 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in 0/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J .Hum. Genet. 2009 Oct;85:427-46). This amino acid position is highly 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.