ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.320G>A (p.Cys107Tyr) (rs142358238)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115173 SCV000186495 likely benign Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Subpopulation frequency in support of benign classification,Other data supporting benign classification
Color RCV000115173 SCV000910674 likely benign Hereditary cancer-predisposing syndrome 2015-10-29 criteria provided, single submitter clinical testing
Counsyl RCV000198992 SCV000792422 uncertain significance Ataxia-telangiectasia syndrome 2017-06-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589242 SCV000861414 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000515352 SCV000611357 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000589242 SCV000149082 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.320G>A at the cDNA level, p.Cys107Tyr (C107Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in the compound heterozygous state with a nonsense variant in one individual with Ataxia-telangiectasia (A-T), whose diagnosis was confirmed by clinical observation and radiation sensitivity testing (Bernstein 2003). This variant was also observed in at least two individuals undergoing hereditary cancer testing (Yorczyk 2014, Yurgelun 2015), and in at least one individual with acute myeloid leukemia (Lu 2015). Hirsch et al. (2008) did not identify ATM Cys107Tyr in a series of 31 African-American individuals with breast cancer, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 2/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Cys107Tyr was observed at an allele frequency of 0.21% in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Cys107Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115173 SCV000576456 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589242 SCV000694251 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The ATM c.320G>A (p.Cys107Tyr) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 17/115942 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001633 (16/9796). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in affected individuals (A-T, BrC, and Lynch syndrome pts) via publications, however in at-least one such report, it was found not to have an associated risk with BrC (Haiman_PLOS Genetics_2013). This study concluded that there is no support for the role of protein-coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. In addition, multiple reputable clinical laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000198992 SCV000254081 uncertain significance Ataxia-telangiectasia syndrome 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 107 of the ATM protein (p.Cys107Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs142358238, ExAC 0.2%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 12673797), acute myeloid leukemia (PMID: 26689913), and suspected Lynch syndrome (PMID: 25980754). It has also been observed in an unaffected individual (PMID: 17333338). ClinVar contains an entry for this variant (Variation ID: 127368). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000198992 SCV000838468 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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