ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.331+1G>A (rs1555055356)

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Total submissions: 5
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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
Invitae RCV000576405 SCV000828879 pathogenic Ataxia-telangiectasia syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 31921190). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 487450). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000777474 SCV000913336 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-14 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 not been reported in individuals affected with hereditary cancer in the literature. 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 2019-11-08 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. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish 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, <span style="font-family:arial,sans-serif">Verhagen MM et al, Neurology <span style="font-family:arial,sans-serif">2009 Aug; 73(6):430-7, Verhagen MM, et al. Hum. Mutat. 2012 Mar; 33(3):561-71<font face="arial, sans-serif">)</font>. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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