Submissions for variant NM_000051.4(ATM):c.331+5G>A

dbSNP: rs752135143

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216445	SCV000274529	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-23	criteria provided, single submitter	clinical testing	The c.331+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the ATM gene. In one study, this alteration was detected as homozygous in two related individuals diagnosed with ataxia-telangiectasia (A-T) and was correlated with decreased ATM protein levels and kinase activity (Verhagen MM et al, Neurology 2009 Aug; 73(6):430-7). This alteration has also been identified in several individuals with A-T as a compound heterozygous state (Morio T et al. Int. J. Hematol., 2009 Nov;90:455-462; Nakamura K et al. Hum. Mutat., 2012 Jan;33:198-208; Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71; Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000410500	SCV000486591	likely pathogenic	Ataxia-telangiectasia syndrome	2016-06-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000761802	SCV000891999	likely pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000410500	SCV001219332	pathogenic	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the ATM gene. It does not directly 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 present in population databases (rs752135143, gnomAD 0.0009%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 19535770, 22006793, 22213089, 23726790). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 230851). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 19535770). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant 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.
3billion	RCV000410500	SCV002572915	pathogenic	Ataxia-telangiectasia syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Splice variant predicted to produce a truncated protein by alternate splicing. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19535770). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 19535770, 22213089, 23726790). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 23726790). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230851 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002494588	SCV002813899	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000761802	SCV004169100	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and published functional studies demonstrate this variant causes skipping of exon 4, with reduced or absent ATM protein and kinase activity (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; van Os et al., 2017); Observed in the homozygous or compound heterozygous state in several individuals with ataxia-telangiectasia (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; Chen et al., 2013; van Os et al., 2017); Observed in the heterozygous state in individuals with prostate or ovarian cancer (Lilyquist et al., 2017; Darst et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also reported as IVS6+5G>A using alternate intron nomenclature; This variant is associated with the following publications: (PMID: 23726790, 22006793, 19535770, 23566627, 22213089, 28126470, 19705055, 30549301, 29288088, 32853339, 29922827, 30850667, 37649078, 28888541)
Baylor Genetics	RCV003469016	SCV004209449	pathogenic	Familial cancer of breast	2023-09-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000410500	SCV004848788	pathogenic	Ataxia-telangiectasia syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The c.331+5G>A variant in ATM has been reported in at least 2 homozygous and 2 compound heterozygous individuals with ataxia-telangiectasia and segregated with disease in at least 1 affected family member (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793, Verhagen 2012 PMID: 22213089, Chen 2013 PMID: 23726790). It has also been reported in ClinVar (Variation ID 230851) but was absent from large population studies. This variant is located in the 5'/3' splice region. Computational tools do not provide strong support for a splicing impact, however, In vitro functional studies (including using patient tissue) support exon 6 (exon 5 on NM000051) skipping (introducing a frameshift) and an impact on ATM function (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793). Loss of function of the ATM gene is an established disease mechanism in autosomal recessive ataxia telangiectasia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ataxia telangiectasia. ACMG/AMP Criteria applied: PM2_supporting, PVS1, PM3_Strong.
Myriad Genetics, Inc.	RCV003469016	SCV004932145	likely pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data, PMID: 17726045]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19535770, 22213089, 23726790].
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000761802	SCV001741181	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000761802	SCV001906252	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000761802	SCV001958220	pathogenic	not provided		no assertion criteria provided	clinical testing