ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4776+2T>A (rs587781927)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412136 SCV000486458 likely pathogenic Ataxia-telangiectasia syndrome 2016-06-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775841 SCV000910312 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775841 SCV001184839 pathogenic Hereditary cancer-predisposing syndrome 2019-11-08 criteria provided, single submitter clinical testing The c.4776+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 30 in the ATM gene. This alteration was seen in multiple, unrelated Japanese patients with ataxia telangiectasia, and RNA analysis demonstrated that it results in skipping of coding exon 30 (designated as exon 33 in this study) (Ejima Y et al. Hum. Genet., 1998 Apr;102:403-8). In addition, a different ATM mutation at this nucleotide position, c.4776+2T>C, was also seen in patients with ataxia telangiectasia and was also shown to result in skipping of coding exon 30 (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62(3):551-61). In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030531 SCV001193479 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000412136 SCV001554526 pathogenic Ataxia-telangiectasia syndrome 2021-03-23 criteria provided, single submitter clinical testing Variant summary: ATM c.4776+2T>A 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by published functional studies although one report provided indirect evidence supporting the skipping of exon 30 (legacy naming as exon 33) without presenting the data (Sasaki_1998). The variant was absent in 249594 control chromosomes. c.4776+2T>A (reported as 4612del165 or IVS33+2T>A) has been reported in the literature in multiple homozygous and compound heterozygous individuals of Japanese ancestry affected with Ataxia-Telangiectasia (example, Ejima_1998, Sasaki_1998) as well as in reports of Japanese carriers with breast cancer (example, Kaneyasu_2020, Momozawa_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one research foundation have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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