ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6988C>G (p.Leu2330Val) (rs148432863)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212054 SCV000149147 likely benign not specified 2018-02-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000587802 SCV000166140 likely benign not provided 2019-02-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115238 SCV000172962 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000212054 SCV000694339 likely benign not specified 2019-08-26 criteria provided, single submitter clinical testing Variant summary: ATM c.6988C>G (p.Leu2330Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250962 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 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, FLOSSIES database (consists of African American and European American women older than 70 years who never had cancer) had several African American women who carried this variant. c.6988C>G has been reported in the literature without strong evidence for causality in individuals affected with Breast Cancer (Teraoka_2001, Tavtigian_2009, Bernstein_2010) and in one individual with Lynch syndrome-associated cancer and/or colorectal polyps (Yurgelun 2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Furthermore, no statistically significant association with the disease was found for this variant in a large breast cancer case-control study (Haiman 2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014). Three laboratories cited the variant as likely benign and three laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000122882 SCV000838587 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587802 SCV000855439 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
Color RCV000115238 SCV000902719 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing

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