ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5319+2T>C (rs1555105842)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565533 SCV000660641 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-30 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Rarity in general population databases (dbsnp, esp, 1000 genomes);Deficient protein function by in vitro/ex vivo assay;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Invitae RCV000801687 SCV000941477 likely pathogenic Ataxia-telangiectasia syndrome 2019-09-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 35 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 individuals affected with ataxia-telangiectasia (PMID: 17124347, 23454770). This variant is also known as IVS37+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 479006). Experimental study has shown that this change in combination with another ATM pathogenic variant showed no ATM protein in individual's derived lymphoblastoid cell line (PMID: 23454770). 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). 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.
Integrated Genetics/Laboratory Corporation of America RCV000801687 SCV001360416 likely pathogenic Ataxia-telangiectasia syndrome 2019-03-01 criteria provided, single submitter clinical testing Variant summary: ATM c.5319+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245606 control chromosomes (gnomAD). c.5319+2T>C has been reported in the literature in heterozygous state with another pathogenic variant (ATM 5692C>T, R1898X), in an individual affected with Ataxia-Telangiectasia (Magliozzi_2006). Protein expression analysis carried out on cells derived from the patient showed zero ATM protein level (Prodosmo_2013). The variant has also been detected in one breast cancer patient (Hauke_2018). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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