ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115160 SCV000186701 benign Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
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
Counsyl RCV000168041 SCV000799612 uncertain significance Ataxia-telangiectasia syndrome 2018-04-30 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000590126 SCV000694231 uncertain significance not provided 2016-09-02 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 4/4 in silico programs (SNPs&Go not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 47/121306 (1/2581), predominantly in the African cohort, 43/10400 (1/241), which exceeds the maximum expected allele frequency for a pathogenic ATM variant of 1/2000 for Breast Cancer. Therefore, this suggests the variant of interest to be a rare polymorphism found in population(s) of African origin. The variant of interest has been reported in multiple individuals via publications with limited information (ie lack of clinical, co-occurrence and co-segregation data), and in one case was detected in a patient with a likely pathogenic BRIP1 mutation (Yurgelun_2015). In addition, multiple reputable clinical laboratories cite the variant with varying classifications "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as VUS-possibly benign until additional information becomes available.
Invitae RCV000168041 SCV000218693 benign Ataxia-telangiectasia syndrome 2018-01-05 criteria provided, single submitter clinical testing

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