Submissions for variant NM_000051.4(ATM):c.4110-9C>G

dbSNP: rs730881367

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474638	SCV000546867	uncertain significance	Ataxia-telangiectasia syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 27 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 21965147). ClinVar contains an entry for this variant (Variation ID: 407567). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000479444	SCV000568321	likely pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Non-canonical splice variant demonstrated to result in abnormal splicing (External communication with Ambry Genetics); This variant is associated with the following publications: (PMID: 21965147)
Ambry Genetics	RCV001021891	SCV001183562	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-05	criteria provided, single submitter	clinical testing	The c.4110-9C>G intronic pathogenic mutation results from a C to G substitution 9 nucleotides upstream from coding exon 27 in the ATM gene. This nucleotide position is not well conserved in available vertebrate species. 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. This mutation was identified along with a second truncating mutation in a patient with a clinical diagnosis of ataxia telangiectasia (Demuth I et al. Neurogenetics, 2011 Nov;12:273-82). RNA analysis from lymphoblastoid cells established from the peripheral blood of this patient reveal that this variant activates a cryptic splice site resulting in an mRNA containing eight additional bases leading to a frame shift. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001021891	SCV001360384	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This variant causes a C>G nucleotide substitution at the -9 position of intron 27 of the ATM gene. The variant is predicted to damage the natural splice acceptor site and create a de novo acceptor site 8 basepairs upstream. Use of the de novo site would be expected to result in a frameshift at the protein level, but this has not been demonstrated experimentally. This variant has been reported to co-occur with ATM c.362T>A (p.Leu121*) in an individual affected with ataxia-telangiectasia in the literature, but the phase of the variants was not reported (PMID: 21965147). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV001021891	SCV001911460	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.4110-9C>G intronic variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is predicted to cause the loss of the natural splicing acceptor of exon 28 but also a new splicing site is created/activated according to the 4 splicing predictors of the set SpliceSiteFinderlike-MaxEntScan-NNSplice-GeneSplicer (PP3). The variant was detected in an ataxia telangiectasia patient, together with the ATM c.362T>A (p.Leu121*) truncating variant (phase unknown), which awards it with 0.5 points as per ClinGen SVI Recommendation for in trans Criterion (PM3_Supporting; PMID: 21965147). According to the authors, the RNA analysis of the variant in the patient RNA found the predicted activation of a cryptic splice site leading to the insertion of the last 8 bp of intron 27, a frameshift and expectedly NMD (PS3_Supporting; PMID: 21965147). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PP3 + PM3_Supporting + PS3_Supporting (PMID: 33280026).
Baylor Genetics	RCV003476060	SCV004204468	likely pathogenic	Familial cancer of breast	2023-10-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003476060	SCV004932186	likely pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21965147]. This variant is expected to disrupt protein structure [Myriad internal data].