ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4776+2_4776+13delTAATAAAAATTT (rs762838462)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000582357 SCV000687568 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000482221 SCV000568671 likely pathogenic not provided 2015-11-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.4776+2_4776+13del12 or IVS31+2_IVS31+13del12 and consists of a deletion of 12 nucleotides from the +2 to +13 positions of intron 31. The normal sequence, with the bases that are deleted in braces, is GAGg[del12]catc, where the capital letters are exonic and lowercase are intronic. This 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. 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. Based on the currently available information, we consider ATM c.4776+2_4776+13del12 to be likely pathogenic.
Invitae RCV000536317 SCV000622530 pathogenic Ataxia-telangiectasia syndrome 2017-05-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 31 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a ATM-related disease. Two different variants affecting this same splice donor site (c.4776+2T>C and c.4776+2T>A) have been determined to be pathogenic (PMID: 9497252, 9600235). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Intron 31 is also referred to as intron 33 in the literature and these variants are also known as IVS33+2T>C, IVS33+2T>A, and 4612del165 in the literature. For these reasons, this variant has been classified as Pathogenic.

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