Submissions for variant NM_000051.4(ATM):c.1066-6T>G

gnomAD frequency: 0.00139  dbSNP: rs201686625

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV001253153	SCV002499287	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.1066-6T>G variant has a GnomAD (v2.1.1) filtering allele frequency of 0.2081% (NFE) which is above the ATM BS1 threshold of .05% (BS1). In silico predictors (SpliceAI Acceptor Loss 0.62; MaxEntScan -2.49) are indeterminate about whether this variant affects splicing. This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 26957, 500031). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel
GeneDx	RCV000488246	SCV000149041	likely benign	not provided	2021-06-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26898890, 28779002, 28643015, 21933854, 10677309, 15101044, 11606401, 25040471, 27067391, 26250988, 18573109, 26662178, 27798748, 27296296, 19781682, 16958054, 27803004, 28627265, 28691344, 16914028, 28652578, 20544271, 30549301, 11830610, 32918381)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003178	SCV000153826	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115132	SCV000183798	likely benign	Hereditary cancer-predisposing syndrome	2019-05-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000488246	SCV000232903	uncertain significance	not provided	2014-09-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488246	SCV000574904	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: PP3, BS2
Genetic Services Laboratory, University of Chicago	RCV000200968	SCV000593476	benign	not specified	2021-03-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000488246	SCV000602558	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115132	SCV000687286	benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200968	SCV000694169	benign	not specified	2019-06-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1066-6T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. Although the variant was reported to be associated with a partial splicing defect (see e.g. Broeks_2000, Dork_2001, Fang_2010), several patient samples were also reported to have second-site mutations that could also affect splicing, therefor the splicing effect of the variant in isolation is currently unclear (Tavtigian_2009, Fievet_2019). The variant allele was found at a frequency of 0.0014 in 270694 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.0024 in the gnomAD database (including 2 homozygotes). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, the variant was reported to be found in the FLOSSIES database in 33/7325 European American women, who were older than age 70 years and have never had cancer. The allele frequency in this cohort is also higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0023 vs. 0.001), further supporting a benign role for the variant. Though the variant has been reported in the literature in homozygous individuals affected with Ataxia Telangiectasia (A-T), these patients carried second-site mutations that were sufficient to explain the A-T phenotype (Tavtigian_2009, Fievet_2019). The variant was also reported in compound heterozygosity, with (potential) pathogenic ATM variants in trans, in an individual affected with breast cancer (Fang_2010) and also in a patient with multiple myeloma and (per authors) an atypical, milder A-T phenotype (Austen_2008). Therefore these reports do not support the association of the variant with A-T. The variant, c.1066-6T>G, also has been reported in the literature in individuals affected with Breast Cancer, however in most of the cases co-occurrence and/or co-segregation data was not provided, therefore these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Moreover, in case-control studies the variant did not have significantly increased risk association with breast cancer (Dork_2001, Bernstein_2006, Ding_2011). One recent case-control study reported the variant with an increased risk for CLL (OR: 3.29), however this analysis had a relatively small sample size and most patients were sporadic cases, thus this risk association might not be reliable (Tiao 2017). Twelve other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS (4x), likely benign (3x) / benign (5x). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000200968	SCV000805489	benign	not specified	2017-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000003178	SCV000838482	likely benign	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000488246	SCV000840913	benign	not provided	2018-08-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000003178	SCV001263699	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253153	SCV001428726	uncertain significance	Familial cancer of breast	2019-06-13	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000488246	SCV002010849	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797991	SCV002042283	likely benign	Breast and/or ovarian cancer	2023-06-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115132	SCV002529707	benign	Hereditary cancer-predisposing syndrome	2020-11-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200968	SCV002760518	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496240	SCV002805757	likely benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000488246	SCV004219908	benign	not provided	2023-01-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000488246	SCV004226227	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	PP1, PM3, PS4_moderate
Myriad Genetics, Inc.	RCV001253153	SCV005083829	likely benign	Familial cancer of breast	2024-04-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Breakthrough Genomics, Breakthrough Genomics	RCV000488246	SCV005230998	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000003178	SCV000023336	uncertain significance	Ataxia-telangiectasia syndrome	2006-11-01	no assertion criteria provided	literature only
True Health Diagnostics	RCV000115132	SCV000787840	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355481	SCV001550381	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.1066-6T>G variant was identified in 51 of 18,694 proband chromosomes (frequency: 0.003) from individuals or families with chronic lymphocatic leukemia, breast or ovarian cancer and was present in 70 of 27,754 control chromosomes (frequency: 0.003) from healthy individuals (Ding 2010, Tiao 2017). The variant was identified in dbSNP (rs201686625) as “with other allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Integrated Genetics and 5 other submitters; as benign by Invitae, Color, Athena Diagnostics and 2 other submitters; and as likely benign by GeneDx and 2 other submitters) and LOVD 3.0 (observed 8x). The variant was identified in control databases in 357 of 266,346 chromosomes (2 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 23,658 chromosomes (freq: 0.0003), Other in 2 of 6198 chromosomes (freq: 0.0003), Latino in 19 of 32,652 chromosomes (freq: 0.0006), European in 286 of 123,010 chromosomes (freq: 0.002), Finnish in 18 of 25,254 chromosomes (freq: 0.0007), and South Asian in 25 of 27,738 chromosomes (freq: 0.0009); it was not observed in the Ashkenazi Jewish or East Asian populations. The variant was identified by our laboratory in multiple patients with pathogenic variants in BRCA2 (including c.1929del, p.Arg645Glufs*15 and c.755_758del, p.Asp252Valfs*24). The variant was also identified in the homozygous state in a patient with ataxia telangiectasia (Dork 2001), for whom alternate pathogenic variants were subsequently identified (Tavtigian 2009). A patient with mild ataxia telangiectasia was found to carry this variant in the compound heterozygous state and had reduced ATM protein expression and kinase activity, indicating this variant does not fully abolish protein expression and function (Austen 2016). Additionally, this variant leads to an increase in exon 11 skipping, although some exon 11 skipping is found in controls who do not carry this variant (Soukupova 2007). The c.1066-6T>G variant is located in the 3' splice region and does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence; variants involving these positions sometimes affect splicing and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488246	SCV001968518	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115132	SCV001977066	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000003178	SCV002092668	likely benign	Ataxia-telangiectasia syndrome	2019-10-30	no assertion criteria provided	clinical testing