ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8786+1G>A (rs17174393)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115269 SCV000149178 pathogenic not provided 2019-11-11 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stankovic 1998, Garcia-Perez 2001, Reiman 2011); Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in the heterozygous state in individuals with a personal or family history including lymphoma and colorectal cancer (Sutton 2015, AlDubayan 2018); Also known as c.8672del115 and IVS62+1G>A; This variant is associated with the following publications: (PMID: 31948886, 29625052, 30612635, 31285527, 21459046, 30549301, 30338439, 29478780, 26681312, 27479817, 8659541, 21792198, 8808599, 8789452, 10980530, 11298136, 12552559, 10817650, 9443866, 9463314, 10330348, 25480502, 21445571)
Counsyl RCV000169303 SCV000220622 likely pathogenic Ataxia-telangiectasia syndrome 2014-08-22 criteria provided, single submitter literature only
Ambry Genetics RCV000220586 SCV000273800 pathogenic Hereditary cancer-predisposing syndrome 2019-11-29 criteria provided, single submitter clinical testing The c.8786+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after intron 59 of the ATM gene. This alteration has been detected in numerous individuals with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Schon K et al. Ann. Neurol. 2019 02;85(2):170-180). In addition, western blot analysis has shown that this alteration results in a truncated ATM protein product (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as pathogenic.
Invitae RCV000169303 SCV000283091 pathogenic Ataxia-telangiectasia syndrome 2020-09-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 60 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs17174393, ExAC 0.003%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 8808599, 10330348, 8659541, 10980530, 9463314, 11298136, 10817650, 21459046, 21792198), and individuals with a family history of breast cancer (PMID: 21445571). This variant is also known as IVS62+1G>A and c.8672del115 in the literature. ClinVar contains an entry for this variant (Variation ID: 127463). 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). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000220586 SCV000682516 pathogenic Hereditary cancer-predisposing syndrome 2020-12-15 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 60 of the ATM gene. RNA studies have shown that this variant causes the skipping of exon 60 (also known as exon 62 in the literature) or the inclusion of the first 14 nucleotides of intron 60 in the RNA transcripts (PMID: 9463314, 10330348, 10980530, 11298136). Both aberrant transcripts are expected to create a frameshift and premature truncation and result in an absent or non-functional protein product. This variant (also known as IVS62+1G>A in the literature) has been reported in many individuals affected with ataxia telangiectasia (PMID: 9463314, 10330348, 10817650, 10980530, 11298136, 12552559, 21792198). This variant has also been identified in 4/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000115269 SCV000805632 pathogenic not provided 2016-11-22 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761159 SCV000891075 pathogenic Malignant glioma 2017-02-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763226 SCV000893858 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169303 SCV000918527 pathogenic Ataxia-telangiectasia syndrome 2018-03-26 criteria provided, single submitter clinical testing Variant summary: ATM c.8786+1G>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: Five predict the variant abolishes a 5 splicing donor site. Multiple publications, Laake_2000 and Stankovic_1998, functionally assessed the variant and found it to affect mRNA splicing. The variant was observed with an allele frequency of 1.2e-05 in 246218 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.2e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.8786+1G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Laake_2000, Stankovic_1998). These data indicate that the variant is very likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000169303 SCV000328305 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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