Submissions for variant NM_000051.4(ATM):c.8786+1G>A

gnomAD frequency: 0.00002  dbSNP: rs17174393

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003467035	SCV004565385	pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a premature stop codon and nonsense mediated decay. The highest minor allele frequency in gnomAD v2.1.1 is 0.00003517 (4/113738) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 26896183, 10817650, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong)
GeneDx	RCV000115269	SCV000149178	pathogenic	not provided	2022-05-19	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); Observed in the heterozygous state in individuals with a personal or family history including lymphoma and colorectal cancer (Sutton 2015, AlDubayan 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS62+1G>A; This variant is associated with the following publications: (PMID: 8789452, 21445571, 25480502, 10330348, 9463314, 9443866, 10817650, 12552559, 11298136, 10980530, 8808599, 21792198, 8659541, 27479817, 29478780, 30338439, 30549301, 21459046, 25525159, 29625052, 31285527, 33436325, 30612635, 26681312, 31948886, 32853339, 26896183)
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	2023-01-10	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). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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 pathogenic.
Invitae	RCV000169303	SCV000283091	pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 60 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs17174393, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). This variant is also known as IVS62+1G>A and c.8672del115. ClinVar contains an entry for this variant (Variation ID: 127463). Studies have shown that disruption of this splice site results in skipping of exon 60 and/or activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000220586	SCV000682516	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-08	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). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 2/53461 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991). 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, part of Exact Sciences	RCV000115269	SCV000805632	pathogenic	not provided	2016-11-22	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, 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	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169303	SCV000918527	pathogenic	Ataxia-telangiectasia syndrome	2021-12-06	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: Four predict the variant abolishes a canonical 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 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000169303	SCV002020664	pathogenic	Ataxia-telangiectasia syndrome	2019-01-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000220586	SCV002527965	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115269	SCV004024616	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467035	SCV004210174	pathogenic	Familial cancer of breast	2023-07-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467035	SCV004931333	likely pathogenic	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
GeneReviews	RCV000169303	SCV000328305	pathogenic	Ataxia-telangiectasia syndrome	2016-10-27	no assertion criteria provided	literature only
Natera, Inc.	RCV000169303	SCV002082758	pathogenic	Ataxia-telangiectasia syndrome	2021-01-19	no assertion criteria provided	clinical testing