Submissions for variant NM_000051.4(ATM):c.3577-1G>C

dbSNP: rs1057517226

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410163	SCV000486943	likely pathogenic	Ataxia-telangiectasia syndrome	2016-09-09	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000708602	SCV000821700	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change occurs 1 nucleotides before exon 25 of the ATM gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Donor and acceptor splice site variants as usual lead to a loss of protein function (PMID: 16199547). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID:371378).
Color Diagnostics, LLC DBA Color Health	RCV000708602	SCV001340194	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This variant causes a G>C nucleotide substitution at the -1 position of intron 24 of the ATM gene. Splice site prediction tools predict 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410163	SCV002287258	likely pathogenic	Ataxia-telangiectasia syndrome	2023-07-28	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 371378). Disruption of this splice site has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 24 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).
Myriad Genetics, Inc.	RCV004022148	SCV004931064	likely pathogenic	Familial cancer of breast	2024-01-22	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.