Submissions for variant NM_000051.4(ATM):c.7629+2T>C

gnomAD frequency: 0.00001  dbSNP: rs786203059

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166196	SCV000216973	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The c.7629+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 50 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. 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. However, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). A published RNA study performed on a heterozygous carrier of this variant identified only 24% of the total transcripts as abnormal (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). This suggests that there may be some normal splicing associated with this variant. Internal RNA studies have also suggested that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000236019	SCV000293660	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in a partial splicing defect leading to multiple transcripts, a majority of which are full-length (Casadei et al., 2019); Identified in individuals with prostate cancer or melanoma (Kaur et al., 2020; Dalmasso et al., 2021); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34262154, 31843900, 23532176, 32694154)
Color Diagnostics, LLC DBA Color Health	RCV000166196	SCV000537623	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 51 of the ATM gene. Splice site tools predict that this variant may have a significant impact on RNA splicing. This variant was reported in an individual with a personal and family history of cancer (PMID: 31843900). Lymphoblasts derived from this person showed that this variant results in exon 51 skipping (part of the FAT domain), use of a cryptic donor site that causes a 4 base insertion and premature stop codon, as well as full length transcript (PMID: 31843900). This variant has been identified in 1/248366 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 Likely Pathogenic.
Invitae	RCV000697479	SCV000826093	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 51 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs786203059, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with a personal or family history of cancer (PMID: 31843900, 34262154). ClinVar contains an entry for this variant (Variation ID: 186579). Studies have shown that disruption of this splice site is associated with altered splicing; however, the splicing effect is incomplete and of unknown impact on protein function (PMID: 31843900, external communication; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000762828	SCV000893186	likely pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001171408	SCV004207717	uncertain significance	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001171408	SCV001251312	pathogenic	Familial cancer of breast	2019-09-01	no assertion criteria provided	research
Natera, Inc.	RCV000697479	SCV001462588	likely pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing