Submissions for variant NM_000051.4(ATM):c.331+1G>A

dbSNP: rs1555055356

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576405	SCV000678177	likely pathogenic	Ataxia-telangiectasia syndrome	2016-12-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576405	SCV000828879	pathogenic	Ataxia-telangiectasia syndrome	2023-08-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 31921190). 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: 487450). Studies have shown that disruption of this splice site results in skipping of exon 4 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	RCV000777474	SCV000913336	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the canonical +1 position of intron 4 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been observed in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 31921190). This variant has also been reported in an individual affected with gastroesophageal junction adenocarcinoma, cervical cancer and parathyroid cancer (PMID: 35078243). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Blueprint Genetics	RCV000788912	SCV000928204	likely pathogenic	not provided	2019-02-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000777474	SCV001181314	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The c.331+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the ATM gene. 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). Another mutation at this donor site, c.331+5G>A, results in the same abnormal splicing event and has been reported in multiple individuals with a clinical diagnosis of ataxia-telangiectasia (A-T) (Nakamura K, et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Morio T, et al. Int. J. Hematol. 2009 Nov; 90(4):455-62, Verhagen MM et al, Neurology 2009 Aug; 73(6):430-7, Verhagen MM, et al. Hum. Mutat. 2012 Mar; 33(3):561-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000788912	SCV002584161	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with pancreatic cancer (Hutchings et al., 2019); This variant is associated with the following publications: (PMID: 31285527, 31921190)
Baylor Genetics	RCV003459414	SCV004207084	pathogenic	Familial cancer of breast	2023-10-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003459414	SCV004932958	likely pathogenic	Familial cancer of breast	2024-01-09	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.