Submissions for variant NM_000051.4(ATM):c.2608A>G (p.Asn870Asp)

gnomAD frequency: 0.00146  dbSNP: rs61734354

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000858203	SCV000149069	likely benign	not provided	2022-06-09	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000115160	SCV000186701	benign	Hereditary cancer-predisposing syndrome	2019-05-15	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168041	SCV000218693	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211984	SCV000694231	benign	not specified	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2608A>G (p.Asn870Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 143226 control chromosomes, predominantly at a frequency of 0.0047 within the African or African-American subpopulation (i.e. 196/42012 alleles) in the gnomAD database (v3 genomes dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4.7 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 African or African-American origin. In addition, this variant has been reported in 23/2559 African American women (i.e. with an allele frequency 0.0045) who are older than age 70 and cancer free (in the FLOSSIES database). c.2608A>G has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported (BRIP1 c.484C>T (p.Arg162X), Yurgelun_2015; BRCA1 c.4065_4068delTCAA (p.Asn1355LysfsX10), in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. benign (n=4) or VUS (n=4)). Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000168041	SCV000799612	uncertain significance	Ataxia-telangiectasia syndrome	2018-04-30	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767896	SCV000898527	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-03-30	criteria provided, single submitter	clinical testing	ATM NM_000051 exon 17 p.Asn870Asp (c.2608A>G): This variant has been reported in the literature in at least 2 individuals with a clinical suspicion of Lynch syndrome. Of note, one of these individuals also carried a loss of function variant in a different gene (Yurgelun 2015 PMID:25980754). This variant is present in 0.4 % (102/24026) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61734354). This variant is present in ClinVar (Variation ID:127355). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000115160	SCV000910623	benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000168041	SCV001138475	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000858203	SCV001143101	benign	not provided	2018-09-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858203	SCV001472928	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing	The ATM c.2608A>G; p.Asn870Asp variant (rs61734354) is reported in a chronic lymphocytic leukemia cohort (Ouillette 2012), a patient with renal cell carcinoma (Wen 2015), and two patients with suspected Lynch syndrome; however, one of these patients also carried a pathogenic truncating BRIP1 variant (Yurgelun 2015). This variant is also reported in the ClinVar database (Variation ID: 127355). It is found in the general African population with an allele frequency of 0.4% (104/24960 alleles) in the Genome Aggregation Database. The asparagine at codon 870 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Ouillette P et al. Incidence and clinical implications of ATM aberrations in chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2012 Dec;51(12):1125-32. Wen W et al. Mutations in the Kinase Domain of the HER2/ERBB2 Gene Identified in a Wide Variety of Human Cancers. J Mol Diagn. 2015 Sep;17(5):487-95. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.
Sema4, Sema4	RCV000115160	SCV002532334	likely benign	Hereditary cancer-predisposing syndrome	2021-03-01	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858203	SCV004220878	benign	not provided	2018-09-04	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115160	SCV005045453	benign	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589558	SCV005083914	likely benign	Familial cancer of breast	2024-05-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354304	SCV001548887	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asn870Asp variant was identified in 3 of 6764 proband chromosomes (frequency: 0.0004) from individuals or families with contralateral breast cancer or colorectal cancer (Bernstein 2010, Yurgelun 2015, Betge 2015). The variant was also identified in dbSNP (ID: rs61734354) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as uncertain significance by GeneDx, Ambry Genetics, Counsyl, and Integrated Genetics/Laboratory Corporation of America), and MutDB. The variant was not identified in the COGR, Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 114 of 277178 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 102 of 24026 chromosomes (freq: 0.004), Latino in 8 of 34418 chromosomes (freq: 0.0002), and European in 4 of 126694 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn870 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
PreventionGenetics, part of Exact Sciences	RCV004549542	SCV004751092	likely benign	ATM-related disorder	2022-03-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).