Submissions for variant NM_000051.4(ATM):c.2467-2A>C

gnomAD frequency: 0.00001  dbSNP: rs1555082050

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583860	SCV000687389	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-21	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the -2 position of intron 16 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Counsyl	RCV000672642	SCV000797767	likely pathogenic	Ataxia-telangiectasia syndrome	2018-02-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672642	SCV001576332	likely pathogenic	Ataxia-telangiectasia syndrome	2022-01-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 16 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 490473). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000583860	SCV004098419	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The c.2467-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 16 in the ATM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV004024631	SCV004933341	likely pathogenic	Familial cancer of breast	2024-01-18	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000672642	SCV005400044	pathogenic	Ataxia-telangiectasia syndrome	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants in this gene result in ataxia-telangiectasia, whereas heterozygous individuals have a greater susceptilbity to breast cancer (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance associated with autosomal dominant susceptibility to breast cancer (MIM#114480; OMIM, PMID: 20301790). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other canonical splice site variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. c.2467-2A>T, c.2467-2A>G, and c.2467-1G>A have been classified as likely pathogenic by clinical laboratories in ClinVar, and c.2467-1G>C and c.2467-2A>T have been observed as compound heterozygous with premature termination codon variants in individuals with ataxia-telangiectasia (PMIDs: 21459046, 22649200). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by three clinical laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign