Submissions for variant NM_000051.4(ATM):c.6096-9_6096-5del

dbSNP: rs879254095

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236366	SCV000293437	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to cause aberrant splicing, resulting in out-of-frame exon skipping (Sandoval et al., 1999; Soukupova et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with ataxia telangiectasia (Sandoval et al., 1999); Observed in a patient with breast cancer (Soukupova et al., 2008); This variant is associated with the following publications: (PMID: 32295079, 9887333, 1849795, 18497957)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793448	SCV000932800	pathogenic	Ataxia-telangiectasia syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 41 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 0.0009%). This variant has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 9887333, 18497957). This variant is also known as c.6096-9delTTCTT. ClinVar contains an entry for this variant (Variation ID: 246092). Studies have shown that this variant results in skipping of exon 42 (also known as exon 44) and introduces a premature termination codon (PMID: 988733, 18497957; Initae). 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	RCV001189626	SCV001356944	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides at the -9 to -5 position of intron 41 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies using carrier-derived RNA have shown that the variant leads to the skipping of exon 42 (also known as exon 44 in the literature) in the RNA transcript (PMID: 9887333, 18497957). The aberrant transcript is predicted to create a premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in the heterozygous state in an individual affected with ataxia telangiectasia (PMID: 9887333). This variant has also been reported in at least one individual affected with breast cancer (PMID: 18497957). This variant has been identified in 1/251274 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.
Sema4, Sema4	RCV001189626	SCV002537594	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-12	criteria provided, single submitter	curation
Ambry Genetics	RCV001189626	SCV002661021	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	The c.6096-9_6096-5delTTCTT intronic variant is located 5 nucleotides upstream from coding exon 41 in the ATM gene. This variant results from a deletion of 5 nucleotides at positions c.6096-9 to c.6096-5. This alteration has been reported in a heterozygous state in an individual with ataxia telangiectasia (Sandoval N et al. Hum. Mol. Genet.1999 Jan;8(1):69-79). This nucleotide region is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Multiple RNA studies have shown that this alteration causes skipping of coding exon 41 (also designated as exon 44) (Sandoval N et al. Hum. Mol. Genet.1999 Jan;8(1):69-79; Soukupova J et al. Oncol. Rep., 2008 Jun;19:1505-10; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003469185	SCV004212072	likely pathogenic	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
CZECANCA consortium	RCV001270951	SCV001451755	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001391205	SCV001593148	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Natera, Inc.	RCV000793448	SCV002078042	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-13	no assertion criteria provided	clinical testing