ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6572+1G>A

dbSNP: rs587779856
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212046 SCV000149140 pathogenic not provided 2014-03-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.6572+1G>A or IVS45+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 45 of the ATM gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also reported in intron 47 using alternative nomenclature, has been reported in a patient with Ataxia Telangiectasia (A-T)who carried a second ATM variant and is considered pathogenic (Birrell 2005). A single variant in the ATM gene has been estimated to increase the relative risk of female breast cancer about 2-fold over the general population (Thompson 2005, Renwick 2006) resulting in a lifetime risk of approximately 25-30%. According to one study, breast cancer risk in women under age 50 who carry one ATM variant is nearly 5 times the age-matched general population risk which translates to approximately a 10% risk (Thompson 2005). This study of 1160 ATM carriers also reported evidence of increased risk for colon cancer. In a recent study of 166 unrelated familial pancreatic cancer patients, 2.4% were identified as carriers of one ATM variant, and in families with 3 or more cases of pancreatic cancer, 4.6% carried an ATM variant (Roberts 2012). Ataxia-Telangiectasia (A-T) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the ATM gene. This multisystem disorder is characterized by progressive neurodegeneration, telangiectasias, immunodeficiency, and increased cancer risks. If an ATM variant carrier'spartner is also heterozygous for an ATM variant, the risk to have a child with A-T is 25% with each pregnancy.
Ambry Genetics RCV000115231 SCV000218014 likely pathogenic Hereditary cancer-predisposing syndrome 2024-05-08 criteria provided, single submitter clinical testing The c.6572+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 44 of the ATM gene. This alteration has been previously identified in one individual with ataxia telangiectasia, however, another ATM mutation was not detected (Birrell GW et al. Hum. Mutat. 2005 Jun; 25(6):593). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl RCV000410003 SCV000486187 likely pathogenic Ataxia-telangiectasia syndrome 2016-04-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000410003 SCV001416621 likely pathogenic Ataxia-telangiectasia syndrome 2023-12-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 45 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 15880721). ClinVar contains an entry for this variant (Variation ID: 127426). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc. RCV004019607 SCV004931229 likely pathogenic Familial cancer of breast 2024-01-30 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.

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