Submissions for variant NM_000051.4(ATM):c.5763-1050A>G

gnomAD frequency: 0.00004  dbSNP: rs774925473

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229886	SCV000282999	pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 38 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs774925473, gnomAD 0.01%). This variant has been observed in individual(s) with atypical ataxia-telangiectasia (characterized by later disease onset and/or slower disease progression and attenuated disease features than classical ataxia-telangiectasia) (PMID: 8755918, 8808599, 10330348, 21792198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 5762ins137, the 4-1-8 variant, IVS40-1050A>G, IVS40+1126A>G, IVS40ins137, and 5763ins130. ClinVar contains an entry for this variant (Variation ID: 3021). Studies have shown that this variant results in 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.
Counsyl	RCV000229886	SCV000485197	pathogenic	Ataxia-telangiectasia syndrome	2016-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000494077	SCV000581456	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The c.5763-1050A>G intronic pathogenic mutation results from an A to G substitution 1050 nucleotides before coding exon 38 in the ATM gene. This mutation is known to activate a cryptic splice donor site that results in the insertion of 137 nucleotides between coding exon 37 and coding exon 38, leading to a premature stop codon that is expected to trigger nonsense-mediated mRNA decay (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Published studies have also shown that a normal mRNA transcript is produced from the affected allele, albeit at significantly reduced levels (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5). This mutation has been observed in multiple ataxia telangiectasia (AT) cohorts in both the homozygous and compound heterozygous state, and due to the preservation of some normal ATM protein expression, AT individuals with at least one copy of this mutation show a relatively less severe phenotype than individuals with classic AT (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). One study showed that two siblings who were homozygous for this mutation and had exceptionally mild AT phenotypes still had approximately 11% of the level of ATM protein expected in normal cells (Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5). This mutation is considered a founder mutation originating in the British Isles, and is seen in the heterozygous state in approximately 15% of AT patients from the UK (Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41). Of note, this alteration is also designated as 5762ins137, IVS40-1050A>G, and IVS40+1126A>G in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Eurofins Ntd Llc (ga)	RCV000724150	SCV000700719	pathogenic	not provided	2016-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000494077	SCV000902857	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -1050 position of intron 38 of the ATM gene. This variant is also known as IVS40-1050A>G, IVS40+1126A>G, IVS40ins137 and 5762ins137 in the literature. RNA studies have shown that this variant activates a cryptic splice donor site that results in the insertion of 137 nucleotides from the intronic sequence into the transcript (= 5762ins137), leading to a frameshift and premature protein truncation (PMID: 8755819; ClinVar SCV000581456.4). This variant is known to be a leaky splice mutation, allowing for the low-level expression of the full-length transcript and normal ATM protein (PMID: 8755819, 10234507, 15174027, 25040471). This variant has been reported in over forty homozygous and compound heterozygous individuals affected with mild, variant form of ataxia-telangiectasia (PMID: 8755918, 10234507, 10330348, 15174027, 21792198, 28008555, 30549301), consistent with the low-level expression of normal ATM protein from the mutant allele that carries this variant. This variant has been observed in multiple individuals affected with breast cancer, pancreatic cancer and melanoma (PMID: 19781682, 28008555, 32255556; Color internal data). This variant has been identified in 5/158620 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.
GeneDx	RCV000724150	SCV001875224	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in two transcripts, one with a 137 nucleotide insertion which results in a frameshift, as well as some normal transcript (McConville et al., 1996; Teraoka et al., 1999); Published functional studies demonstrate a damaging effect: cells from individuals carrying this variant have been shown to have reduced ATM protein levels and ATM kinase activity compared to wildtype (Izatt et al., 1999; Stewart et al., 2001; Sutton et al., 2004; Reiman et al., 2011; Taylor et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 9463314, 23143971, 19823873, 17586848, 25040471, 21459046, 32623769, 19535770, 11382771, 15174027, 20301790, 8755918, 10234507, 10330348, 28008555, 15928302, 12082606, 30549301, 26896183, 32255556, 21792198)
CeGaT Center for Human Genetics Tuebingen	RCV000724150	SCV001961310	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: PM3:Very Strong, PM2, PS3:Supporting
Fulgent Genetics, Fulgent Genetics	RCV002496239	SCV002812511	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000229886	SCV003800812	pathogenic	Ataxia-telangiectasia syndrome	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5763-1050A>G is located at a deep intronic position with several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in the inclusion of 137 base pairs of intronic sequence that is predicted to introduce a premature stop codon leading to a truncated protein (McConville_1996). The variant allele was found at a frequency of 2.4e-05 in 127224 control chromosomes. c.5763-1050A>G has been widely reported in the literature as a biallelic genotype in multiple individuals affected with milder features of Ataxia-Telangiectasia (example, Sutton_2004, McConville_1996). 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149561	SCV003837846	likely pathogenic	Breast and/or ovarian cancer	2023-01-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466789	SCV004208407	pathogenic	Familial cancer of breast	2024-03-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003466789	SCV004930785	pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8755918, 11382771]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21792198, 8755918, 11382771, 26896183, 30549301].
OMIM	RCV000003157	SCV000023315	pathogenic	Ataxia - telangiectasia variant	2004-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000229886	SCV000328266	not provided	Ataxia-telangiectasia syndrome		no assertion provided	literature only
Natera, Inc.	RCV000229886	SCV001452329	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739283	SCV005361212	pathogenic	ATM-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The ATM c.5763-1050A>G variant is predicted to interfere with splicing. This variant, also known as 5762ins137, has been reported in the homozygous and compound heterozygous states in multiple unrelated individuals with ataxia telangiectasia (Table 3, McConville et al. 1996. PubMed ID: 8755918; Table SI, Jackson et al 2016. PubMed ID: 26896183; Supplementary Table 1, Schon et al 2019. PubMed ID: 30549301). In vitro studies show this variant activates a leaky cryptic splice site that introduces a 137 bp insertion of intronic sequence into affected ATM transcripts, although a small amount of normal ATM transcript and protein is still produced likely resulting in the milder phenotypic presentation seen in patients with ataxia telangiectasia (McConville et al 1996. PubMed ID: 8755918; Stewart GS et al 2001. PubMed ID: 11382771). This variant has also been reported in individuals with breast cancer and pancreatic cancer (Table S2, Tavtigian et al. 2009 PubMed ID: 19781682; Table 2, Pritzlaff et al 2016. PubMed ID: 28008555, Supplementary Table 2, Cremin C et al 2020. PubMed ID: 32255556). This variant is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3021/). Taken together, this variant is interpreted as pathogenic.