Submissions for variant NM_000051.4(ATM):c.8268G>T (p.Lys2756Asn)

dbSNP: rs1555128642

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564312	SCV000665610	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-03-25	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000564312	SCV001347287	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001213681	SCV001385326	uncertain significance	Ataxia-telangiectasia syndrome	2023-07-31	criteria provided, single submitter	clinical testing	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. Variants that disrupt 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. 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. ClinVar contains an entry for this variant (Variation ID: 481301). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). 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). This variant also falls at the last nucleotide of exon 56, which is part of the consensus splice site for this exon.
GeneDx	RCV003229841	SCV003927773	likely pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	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)
Baylor Genetics	RCV003465195	SCV004210107	uncertain significance	Familial cancer of breast	2023-07-31	criteria provided, single submitter	clinical testing