ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2932T>C (p.Ser978Pro) (rs139552233)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115167 SCV000172932 benign Hereditary cancer-predisposing syndrome 2017-10-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Athena Diagnostics Inc RCV000584904 SCV000840931 likely benign not provided 2017-09-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000584904 SCV000692731 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Color RCV000115167 SCV000910564 benign Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
Counsyl RCV000119220 SCV000793508 likely benign Ataxia-telangiectasia syndrome 2017-08-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000211991 SCV000343835 likely benign not specified 2016-07-22 criteria provided, single submitter clinical testing
GeneDx RCV000211991 SCV000149076 benign not specified 2017-05-17 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.
GeneKor MSA RCV000115167 SCV000821843 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211991 SCV000694240 likely benign not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: ATM c.2932T>C (p.Ser978Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00089 in 277368 control chromosomes, predominantly at a frequency of 0.005 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. This variant has been reported in multiple affected individuals with classical AT, classical Hodgkins lymphoma, B-NHL, BrC, etc. Among them the one patient with classical AT also carried another ATM variant c.8395-8404del10, and no residual ATM activity was detected via western blot in this patient sample and only about 10% expressed ATM protein detected compared to WT (Carney_2012). However, the possibility of an undetected second variant causing AT in this patient cannot be ruled out. A study evaluating the Rate Ratio of asynchronus contralateral breast cancer associated with ATM gene mutation carrier status found a non-statistically significant risk of contralateral breast cancer for missense variants in the ATM gene (RR 1.2, 95% CI = 0.8 to 1.7) (Bernstein_2010). This low RR and a 95% CI overlapping 1.0 indicate very little confidence in the assertion of association with breast cancer. Nine 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 (6 benign/likely benign, 3 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000119220 SCV000153964 benign Ataxia-telangiectasia syndrome 2018-01-03 criteria provided, single submitter clinical testing
Mendelics RCV000119220 SCV000838514 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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