ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2251-4A>G (rs786202935)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166010 SCV000216769 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-06 criteria provided, single submitter clinical testing The c.2251-4A>G intronic variant results from an A to G substitution 4 nucleotides upstream from coding exon 14 in 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 create a new alternate splice acceptor site. 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.
GeneDx RCV000658621 SCV000569657 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.2251-4A>G or IVS14-4A>G and consists of an A>G nucleotide substitution at the -4 position of intron 14 of the ATM gene. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.2251-4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000628167 SCV000749060 uncertain significance Ataxia-telangiectasia syndrome 2019-06-03 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186418). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658621 SCV000780401 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
GeneKor MSA RCV000166010 SCV000821835 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166010 SCV001353180 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-28 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -4 position of intron 14 of the ATM gene. Splice site prediction tools suggest that this variant may create a new splice acceptor site and have a significant impact on RNA splicing. The use of the new splice acceptor site has been observed in a study using carrier-derived RNA, although the wild-type transcript was also observed, suggesting the impact may be incomplete (PMID: 32748564). The aberrant RNA transcript is expected to create a premature translation stop signal and result in an absent or non-functional protein product. Abnormal RNA splicing has also been reported in ClinVar (ClinVar variation ID: 186418). This variant has been reported in trans with another pathogenic splice ATM variant (c.3576G>A) in three siblings of a family (PMID: 32748564). One male sibling is affected with late-onset progressive ataxia in his 30s. Two female siblings are affected with breast cancer at the age of 39 and 40 years and one of them has shown severe reaction post-radiotherapy. Another female sibling of the family who is heterozygous for this variant is unaffected at the age of 45. This variant has been reported in other individuals with personal and/or family history of breast cancer (PMID: 31159747; doi: 10.7197/cmj.vi.623656). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. The incomplete impact on RNA splicing and lack of classic ataxia telangiectasia phenotype in carriers suggest that this variant may be hypomorphic. Medical management should be considered based on the individual’s personal and family history.

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