ClinVar Genomic variation as it relates to human health

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2067 of the ATM protein (p.Ala2067Asp). This variant is present in population databases (rs397514577, gnomAD 0.0009%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 9887333, 22345219, 25914063; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39749). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 25077176). For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces alanine with aspartic acid at codon 2067 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). This variant has been reported in multiple individuals affected with breast cancer (PMID: 20305132, 26898890; Color internal data) and pancreatic cancer (Color internal data). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with typical or mild ataxia telangiectasia (PMID: 9887333, 22345219, 25037873, 25077176, 25914063). Lymphoblastoid cells isolated from the homozygous carriers have shown absent to trace levels of ATM protein, reduced ATM kinase activity, and increased sensitivity to radiation, indicating reduced capacity to repair DNA damage (PMID: 22345219, 25077176). This variant has been identified in 1/251316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19650357, 22345219, 25077176]. Functional studies indicate this variant impacts protein function [PMID: 19650357, 25077176].

The p.A2067D pathogenic mutation (also known as c.6200C>A), located in coding exon 42 of the ATM gene, results from a C to A substitution at nucleotide position 6200. The alanine at codon 2067 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in two individuals/families with ataxia-telangiectasia (Sandoval N et a. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Dawson AJ et al. Am. J. Med. Genet. 2015 Aug;167A(8):1937-9). This alteration has also been shown to segregate with primary-appearing dystonia in homozygous individuals from three Canadian Mennonite families (Saunders-Pullman R et al. Neurology. 2012 Feb; 78(9):649-57). Additionally, functional assays demonstrated that this alteration results in reduced protein expression, absent autophosphorylation, and diminished transphorphylation of downstream ATM targets (Nakamura K et al. Mol Genet Genomic Med. 2014 Jul; 2(4):332-40). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This amino acid position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, this variant is unlikely to be causative of classical ataxia-telangiectasia; however, it may be associated with dystonia and may lead to increased risk of developing ATM-related cancer. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

According to the ClinGen ACMG ATM v1.3.0 criteria we chose these criteria: PS3 (medium pathogenic): Nakamura 2014 (PMID: 25077176): cell line with mutated ATM cDNA showed a trace-to-absent transphosphorylation of downstream ATM targets & ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein + Ambry Genetics (Accession: SCV000217431.8): Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). , PM2 (supporting pathogenic): V2: 0,0004%, 1 x gefunden; , PM3 (very strong pathogenic): Found in multiple cases of AT phenotype, confirmed in trans (e.g. PMID: 25077176 --> Of the 10 carriers, 6 were homozygous and 4 were compound heterozygotes with ATM pathogenic truncating variants and segregated in trans).

The ATM p.Ala2067Asp variant was identified in 64 of 23034 proband chromosomes (frequency: 0.003) from individuals or families with atypical or “variant-Ataxia Telangiectasia”, breast and ovarian cancer and was not identified in 7976 control chromosomes from healthy individuals (Sandoval 1999, Saunders-Pullman 2012, Lu 2019). The variant was identified in dbSNP (rs397514577) as “with pathogenic allele”, ClinVar (interpreted as pathogenic by Invitae and 4 others, likely pathogenic by Color and 1 other) and LOVD 3.0 (observed 11x). The variant was identified in control databases in 1 of 246,124 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111,648 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The homozygous variant was observed in 3 families with 12 affected people. Patients presented with a variant form of Ataxia Telangiectasia, a milder form of the disease, and 8 of the 12 homozygous carriers had a malignancy later in life including stomach, prostate, myeloid leukemia and lymphoma (Saunders-Pullman 2012, Nakamura 2014). Of the 10 carriers, six were homozygous and 4 were compound heterozygotes with ATM pathogenic variants (p.Arg1898*, p.Glu1978* and p.Val1268*) and segregated in trans (Nakamura 2014). Western blot of lymphoblastoid cell lines derived from these patients had decreased expression of ATM protein. Additionally, site directed mutagenesis experiments that introduced the homozygous variant had low levels of ATM protein in vitro. The presence of the variant also decreased kinase activity by ATM (Nakamura 2014). The p.Ala2067 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Ala2067Asp variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, 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 pathogenic role for this variant. This variant is classified as likely pathogenic.