ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2608A>G (p.Asn870Asp) (rs61734354)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000858203 SCV000149069 likely benign not provided 2021-06-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26320869, 25980754, 26296696, 28135145, 23555315, 20305132)
Ambry Genetics RCV000115160 SCV000186701 benign Hereditary cancer-predisposing syndrome 2019-05-15 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Insufficient or conflicting evidence;No disease association in small case-control study;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000168041 SCV000218693 benign Ataxia-telangiectasia syndrome 2020-12-04 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 2017-10-10 criteria provided, single submitter clinical testing ATM NM_000051.3 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 Health, Inc RCV000115160 SCV000910623 benign Hereditary cancer-predisposing syndrome 2020-12-10 criteria provided, single submitter clinical testing
Mendelics RCV000168041 SCV001138475 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000858203 SCV001143101 benign not provided 2018-09-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286368 SCV001472928 uncertain significance none 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.
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.

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