Submissions for variant NM_000051.4(ATM):c.8268G>A (p.Lys2756=)

dbSNP: rs1555128642

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001733362	SCV001983438	uncertain significance	not specified	2021-09-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8268G>A (p.Lys2756Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, while one predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250702 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8268G>A in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001806252	SCV002051848	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	clinical testing	This variant is a synonymous variant located in the terminal guanine of exon 56 of the ATM gene. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, RNA functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032729	SCV002168977	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-24	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with ATM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 2756 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. This variant also falls at the last nucleotide of exon 56, which is part of the consensus splice site for this exon. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies.
Ambry Genetics	RCV001806252	SCV003866507	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-18	criteria provided, single submitter	clinical testing	The c.8268G>A variant (also known as p.K2756K), located in coding exon 55 of the ATM gene, results from a G to A substitution at nucleotide position 8268. This nucleotide substitution does not change the Lysine at codon 2756. 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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004762174	SCV005373748	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-11	criteria provided, single submitter	curation	PVS1(RNA): RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry Genetics internal data/communication); According to the ClinGen ACMG ATM v1.3.0 criteria we chose these criteria: PVS1 (very strong pathogenic): PVS1(RNA): RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data): Anfrage an Ambry Genetics ergab folgende Antwort: Ambry RNA studies detected substantial aberrant splicing resulting in exon skipping (r.8152_8268del) associated with this variant. This in frame event occurs in the kinase (FATKIN) domain and is considered critical for protein function. Our assay was performed on blood samples and we do not use NMD inhibitors. NMD is known to be relatively inactive in blood cells, and we are routinely able to detect transcripts that contain premature stop codons for most genes. We cannot release details regarding quantitation because our assay isn’t validated as a quantitative assay. --> laut ATM PVS1/PVS1(RNA) Guide --> PVS1_VST, PM2 (supporting pathogenic): absent from gnomAD