Submissions for variant NM_000051.4(ATM):c.4776+2T>C

dbSNP: rs587781927

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130284	SCV000185129	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The c.4776+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 30 in the ATM gene. This alteration has previously reported in multiple families with ataxia-telangiectasia, and it has been shown to lead to aberrant splicing with no detectable levels of ATM protein production (Mitui M et al. Hum. Mutat. 2003; 22:43-50; Gilad S et al. Am. J. Hum. Genet. 1998; 62:551-61; Teraoka SN et al. Am. J. Hum. Genet. 1999; 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). Of note, this alteration is also designated as IVS33+2T>C in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000235350	SCV000293433	pathogenic	not provided	2021-12-27	criteria provided, single submitter	clinical testing	Canonical splice site variant resulting in skipping of exon 31 (Velazquez 2020); Reported in the homozygous and compound heterozygous state in individuals with ataxia-telangiectasia (Curry 1989, Gilad 1998, Mitui 2003); Functional studies showed a cell line with this variant in the homozygous state exhibited radiosensitivity consistent with classic ataxia-telangiectasia cell lines (Curry 1989, Gilad 1998); Observed in the heterozygous state in an individual with a personal and family history of ATM-related cancers (Velazquez 2020); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as IVS33+2T>C; This variant is associated with the following publications: (PMID: 21445571, 12815592, 15279807, 10330348, 25525159, 9497252, 31019026, 32756499, 2491181)
Counsyl	RCV000003170	SCV000794146	pathogenic	Ataxia-telangiectasia syndrome	2017-09-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003170	SCV000836117	pathogenic	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587781927, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 9497252, 12815592). 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 IVS33+2T>C. ClinVar contains an entry for this variant (Variation ID: 141672). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects ATM function (PMID: 2491181, 9497252). Studies have shown that disruption of this splice site results in skipping of exon 31, but is expected to preserve the integrity of the reading-frame (PMID: 9497252; Invitae). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000003170	SCV000838546	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003170	SCV000918553	pathogenic	Ataxia-telangiectasia syndrome	2018-07-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4776+2T>C 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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 244642 control chromosomes. c.4776+2T>C has been reported in the literature in at least two individuals affected with Ataxia-Telangiectasia, one of whom is homozygous for the variant with classic A-T with microcephaly and intellectual disability (Gilad_1998). These data indicate that the variant may be associated with disease. Gilad et al. also report experimental evidence suggesting a loss of ATM protein product in the patient's fibroblast cell line, though the data was not presented for review. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Furthermore, c.4776+2T>A has also been reported to associate with Ataxia-Telangiectasia. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000003170	SCV000996056	pathogenic	Ataxia-telangiectasia syndrome	2017-02-17	criteria provided, single submitter	clinical testing	The c.4776+2T>C canonical splice donor site variant is predicted to cause abnormal gene splicing. This variant, also known as IVS33+2T>C, has been previously reported in the homozygous and compound heterozygous state in individuals with Ataxia-Telangiectasia (AT) (PMID: 9711876). Functional studies showed that this variant led to in-frame skipping of exon 30, previously referred to as exon 32, and a cell line with this variant in the homozygous state exhibited radiosensitivity (PMID: 9497252, 2491181). Based on the combined evidence, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130284	SCV001347405	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant leads to the skipping of exon 31, which is expected to result in an in-frame deletion of 55 amino acids (PMID: 9497252, 32756499). Functional studies have shown that the fibroblast cell line derived from a homozygous carrier of this variant exhibits increased radiosensitivity (PMID: 9497252, 2491181). This variant (also known as IVS33+2T>C in the literature) has been reported in the homozygous and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 12815592, 2491181). This variant has also been reported in an individual affected with breast and ovarian cancer (PMID: 32756499). This variant has been identified in 1/249594 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.
CeGaT Center for Human Genetics Tuebingen	RCV000235350	SCV001371325	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467137	SCV004212053	pathogenic	Familial cancer of breast	2023-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467137	SCV004932286	likely pathogenic	Familial cancer of breast	2024-01-24	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.
OMIM	RCV000003170	SCV000023328	pathogenic	Ataxia-telangiectasia syndrome	1998-03-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000003170	SCV002075287	pathogenic	Ataxia-telangiectasia syndrome	2021-09-02	no assertion criteria provided	clinical testing