This missense variant replaces lysine with asparagine at codon 2756 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant changes the G nucleotide at the end of exon 56 and is predicted to impact the intron 56 splice donor site. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar Accession: SCV000665610.4). This variant has been reported in individuals affected with early onset breast cancer or prostate cancer (communication with an external laboratory; ClinVar SCV001385326.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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 c.8268G>T variant (also known as p.K2756N), located in coding exon 55 of the ATM gene, results from a G to T substitution at nucleotide position 8268. The amino acid change results in lysine to asparagine at codon 2756, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 55, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 2756 of the ATM protein (p.Lys2756Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 481301). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of skipping of exon 56, but is expected to preserve the integrity of the reading-frame (internal data). This variant disrupts a region of the ATM protein in which other variant(s) (p.Gln2730Pro) have been determined to be pathogenic (PMID: 16189143, 19431188, 22869595). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Alters the last nucleotide of the in-frame exon and is predicted to alter the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176)

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].