ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211984 SCV000149069 uncertain significance not specified 2017-09-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.2608A>G at the cDNA level, p.Asn870Asp (N870D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). This variant has been identified in two individuals with a Lynch syndrome-associated cancer and/or colon polyps, one of whom also carried a truncating variant in BRIP1 (Yurgelun 2015). ATM Asn870Asp was observed with an allele frequency of 0.4% in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asn870Asp occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Asn870Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115160 SCV000186701 benign Hereditary cancer-predisposing syndrome 2019-05-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign) ;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 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 RCV000115160 SCV000910623 benign Hereditary cancer-predisposing syndrome 2015-12-10 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

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