Submissions for variant NM_000051.4(ATM):c.901+1G>A

gnomAD frequency: 0.00002  dbSNP: rs748840480

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166407	SCV000217201	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing	The c.901+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the ATM gene. This alteration was identified in conjunction with a truncating ATM mutation in an individual diagnosed with ataxia-telangiectasia (Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50). This alteration was also reported in a male diagnosed with breast cancer and an individual diagnosed with ovarian cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586; Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163(2):383-390). This alteration is also known as IVS9+1G>A in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205735	SCV000260474	pathogenic	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs748840480, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with ATM-related conditions (PMID: 8321536, 12815592, 21665257, 28281021, 31206626). ClinVar contains an entry for this variant (Variation ID: 186761). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515230	SCV000611170	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000205735	SCV000799901	pathogenic	Ataxia-telangiectasia syndrome	2018-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000205735	SCV000918578	pathogenic	Ataxia-telangiectasia syndrome	2018-12-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.901+1G>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: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 271632 control chromosomes (gnomAD). The variant, c.901+1G>A, has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Mitui_2003, Micol_2011, Du_2008) and one ovarian cancer (Crawford_2017) where it was found together with the pathogenic variant PALB2 c.2167_2168delAT (p.Met723fsX21). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166407	SCV001735827	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the ATM gene. This variant is also known as IVS9+1G>A in the literature. Functional studies using patient-derived lymphoblastoid cells showed skipping of exon 7 and premature protein termination (PMID: 18321536). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 12815592, 18321536). This variant also has been reported in an individual affected with male breast cancer (PMID: 28008555). This variant has been identified in 5/276176 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 Pathogenic.
Sema4, Sema4	RCV000166407	SCV002530636	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-24	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000205735	SCV003811112	pathogenic	Ataxia-telangiectasia syndrome	2022-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474877	SCV004204390	pathogenic	Familial cancer of breast	2024-03-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003474877	SCV004931255	likely pathogenic	Familial cancer of breast	2024-01-11	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.
Natera, Inc.	RCV000205735	SCV001456868	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing