Submissions for variant NM_000051.4(ATM):c.4437-1G>C

gnomAD frequency: 0.00001  dbSNP: rs759520465

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216400	SCV000275817	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	The c.4437-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 29 of the ATM gene. This alteration has been reported in a homozygous state in a Hispanic-American individual with classic ataxia-telangiectasia (Mitui M et al. Hum. Mutat. 2003 Jul; 22(1):43-50). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
GeneDx	RCV000486776	SCV000568323	pathogenic	not provided	2022-05-24	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS31-1G>C; This variant is associated with the following publications: (PMID: 12815592)
Invitae	RCV000530451	SCV000622501	pathogenic	Ataxia-telangiectasia syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 29 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs759520465, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with clinical features of ataxia-telangiectasia (PMID: 12815592; Invitae). This variant is also known as IVS31-1G>C. ClinVar contains an entry for this variant (Variation ID: 231843). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000530451	SCV000798327	likely pathogenic	Ataxia-telangiectasia syndrome	2018-03-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216400	SCV001340523	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-11-25	criteria provided, single submitter	clinical testing	This variant causes a G>C nucleotide substitution at the -1 position of intron 29 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant (as known as IVS31-1G>C) has been reported in homozygous state in 1 individual affected with Ataxia-telangiectasia (PMID: 12815592). This variant has been identified in 1/251072 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Sema4, Sema4	RCV000216400	SCV002534778	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
Baylor Genetics	RCV003469042	SCV004210067	pathogenic	Familial cancer of breast	2023-08-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469042	SCV004933531	likely pathogenic	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.