Submissions for variant NM_000051.4(ATM):c.3993+2T>C

dbSNP: rs2135710273

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377633	SCV001575016	pathogenic	Ataxia-telangiectasia syndrome	2022-10-28	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 10980530, 12815592, 30287823). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as 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: 1066594). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 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).
Ambry Genetics	RCV003169934	SCV003858406	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	The c.3993+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 25 of the ATM gene. This variant was present in 0/1005 Japanese pancreatic cancer patients and in 2/23705 controls (Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This alteration was also observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was not observed in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). This nucleotide position is highly conserved in available vertebrate species. 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 donor site and may result in the creation or strengthening of a novel splice donor site. 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. In addition, +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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV004037631	SCV004931875	likely pathogenic	Familial cancer of breast	2024-01-23	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.
Fulgent Genetics, Fulgent Genetics	RCV005040236	SCV005681276	likely pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-05-01	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003169935	SCV002758093	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research