Submissions for variant NM_000051.4(ATM):c.4776+2T>A

dbSNP: rs587781927

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412136	SCV000486458	likely pathogenic	Ataxia-telangiectasia syndrome	2016-06-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775841	SCV000910312	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	clinical testing	This variant causes a T to A nucleotide substitution at the +2 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a number of unrelated Japanese individuals affected with breast cancer (PMID: 32566746, 30287823), pancreatic cancer (PMID: 32980694; Color Health internal data), prostate cancer (PMID: 31214711), ataxia-telangiectasia (PMID: 9600235, 9711876), as well as in healthy controls (PMID: 30287823, 32980694). 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.
Ambry Genetics	RCV000775841	SCV001184839	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-28	criteria provided, single submitter	clinical testing	The c.4776+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 30 in the ATM gene. This alteration was seen in multiple, unrelated Japanese patients with ataxia-telangiectasia, and RNA analysis demonstrated that it results in skipping of coding exon 30 (designated as exon 33 in this study) (Ejima Y et al. Hum. Genet., 1998 Apr;102:403-8). In addition, a different ATM mutation at this nucleotide position, c.4776+2T>C, was also seen in patients with ataxia-telangiectasia and was also shown to result in skipping of coding exon 30 (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62(3):551-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030531	SCV001193479	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412136	SCV001554526	pathogenic	Ataxia-telangiectasia syndrome	2021-03-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4776+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by published functional studies although one report provided indirect evidence supporting the skipping of exon 30 (legacy naming as exon 33) without presenting the data (Sasaki_1998). The variant was absent in 249594 control chromosomes. c.4776+2T>A (reported as 4612del165 or IVS33+2T>A) has been reported in the literature in multiple homozygous and compound heterozygous individuals of Japanese ancestry affected with Ataxia-Telangiectasia (example, Ejima_1998, Sasaki_1998) as well as in reports of Japanese carriers with breast cancer (example, Kaneyasu_2020, Momozawa_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one research foundation have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412136	SCV002230922	pathogenic	Ataxia-telangiectasia syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ATM-related conditions (PMID: 9497252, 9600235, 12815592, 31214711, 32566746). ClinVar contains an entry for this variant (Variation ID: 371007). Studies have shown that disruption of this splice site results in skipping of exon 31, also published as exon 33, but is expected to preserve the integrity of the reading-frame (PMID: 9711876). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004022141	SCV004932866	likely pathogenic	Familial cancer of breast	2024-01-24	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.
Baylor Genetics	RCV004022141	SCV005057098	pathogenic	Familial cancer of breast	2024-01-04	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003168593	SCV002758268	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research