Submissions for variant NM_000051.4(ATM):c.3432G>A (p.Leu1144=)

gnomAD frequency: 0.00001  dbSNP: rs1060501625

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476703	SCV000546919	pathogenic	Ataxia-telangiectasia syndrome	2024-03-21	criteria provided, single submitter	clinical testing	This sequence change affects codon 1144 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 may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of ataxia-telangiectasia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 407599). Studies have shown that this variant results in skipping of partial exon 24 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001177305	SCV001341492	likely benign	Hereditary cancer-predisposing syndrome	2019-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000476703	SCV002500650	likely pathogenic	Ataxia-telangiectasia syndrome	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3432G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, internal evidence obtained from patient-derived RNA splicing studies demonstrated that a majority of transcripts with this variant encoded a partial deletion of exon 24, predicted to result in nonsense mediated decay (Labcorp, formerly Invitae). The variant was absent in 251106 control chromosomes. c.3432G>A has been reported in the compound heterozygous state in at least 1 individual affected with breast cancer and clinical features of Ataxia-Telangiectasia (Labcorp, formerly Invitae). ClinVar contains an entry for this variant (Variation ID: 407599). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001177305	SCV005038300	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	The c.3432G>A variant (also known as p.L1144L), located in coding exon 23 of the ATM gene, results from a G to A substitution at nucleotide position 3432. This nucleotide substitution does not change the leucine at codon 1144. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004591303	SCV005080026	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Myriad Genetics, Inc.	RCV004591302	SCV005083138	benign	Familial cancer of breast	2024-05-14	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Natera, Inc.	RCV000476703	SCV002080407	uncertain significance	Ataxia-telangiectasia syndrome	2021-09-16	no assertion criteria provided	clinical testing