Submissions for variant NM_000051.4(ATM):c.7089G>C (p.Lys2363Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002367255	SCV002663056	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-24	criteria provided, single submitter	clinical testing	The c.7089G>C variant (also known as p.K2363N), located in coding exon 47 of the ATM gene, results from a G to C substitution at nucleotide position 7089. The amino acid change results in lysine to asparagine at codon 2363, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 47, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in an in-frame deletion of coding exon 47 impacting a critical functional domain, and is expected to result in loss of function due to an abnormal transcript (Ambry internal data). As such, this alteration is interpreted as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003607482	SCV004551254	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change affects codon 2363 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1757070). 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 variant results in skipping of exon 48, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in skipping of exon 48 have been determined to be pathogenic (PMID: 26896183, 31843900). This suggests that this variant may also be clinically significant and likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.