Submissions for variant NM_000051.4(ATM):c.2639-384A>G

gnomAD frequency: 0.00003  dbSNP: rs1131691154

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000493875	SCV000581450	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The c.2639-384A>G pathogenic intronic mutation results from an A to G substitution 384 nucleotides upstream from coding exon 17 in the ATM gene. This alteration has been detected in conjunction with pathogenic ATM variants in individuals affected with ataxia-telangiectasia (Nakamura K et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730, Gu C et al. Clin Chim Acta, 2021 Dec;523:6-9). RNA studies have shown that this alteration creates a cryptic splice donor site and leads to the insertion of a 58-bp pseudoexon into the transcript, which is anticipated to result in nonsense mediated RNA decay (Nakamura K et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000493875	SCV001343706	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the -384 position of intron 17 of the ATM gene. Functional RNA studies have shown that this variant causes retention of 58 base pairs from intron 17, creating a frameshift and premature translation stop signal (PMID: 22006793, 31050087). This variant has been reported in the compound heterozygous state with known pathogenic ATM variants in individuals affected with autosomal recessive ataxia-telangiectasia, indicating that this variant contributes to disease (PMID: 22006793, 31050087, 34453918). This variant has also been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001271168	SCV001478803	likely pathogenic	Ataxia-telangiectasia syndrome	2021-01-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2639-384A>G alters a non-conserved nucleotide located deep within intron 17 of the ATM gene. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic intronic 5' splice donor site. In alignment with the computational predictions, at least two publications report experimental evidence that this variant affects mRNA splicing by activating a cryptic intronic 3' splice acceptor site in addition to the cryptic intronic 5' splice donor site, resulting in the insertion of a 58 bp pseudoexon exon in the transcript (Nakamura_2012, Fievet_2018). This corresponds to a transcript named r.2638_2639ins[2639442_2639385] as determined by RNA sequencing and is predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, p.(Gly880Glufs*15) (Fievet_2018), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 31396 control chromosomes (gnomAD). c.2639-384A>G has been reported in the literature in compound heterozygosity with another large genomic deletion in two individuals affected with Ataxia-Telangiectasia from a Japanese family (Nakamura_2012). These data indicate that the variant may be associated with disease. Three 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 likely pathogenic. One submitter cites overlapping evidence utilized in the context of this evaluation further supported by internal data (not presented) corroborating the reported splicing impact. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001271168	SCV001576439	pathogenic	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 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 (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 22006793, 31050087, 34453918). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 429070). Studies have shown that this variant results in in retention of 58 bases from intron 17 (also known as intron 18) and introduces a premature termination codon (PMID: 22006793, 31050087; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000493875	SCV002532378	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	curation
Baylor Genetics	RCV003464062	SCV004207033	likely pathogenic	Familial cancer of breast	2023-10-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003464062	SCV004930791	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22006793, 31050087, 34453918]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 22006793, 31050087, 34453918].
Natera, Inc.	RCV001271168	SCV001452044	likely pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing