ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2804C>T (p.Thr935Met) (rs3218708)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131651 SCV000186678 likely benign Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
GeneDx RCV000211988 SCV000209713 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.2804C>T at the cDNA level, p.Thr935Met (T935M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). ATM Thr935Met was observed in breast cancer cases as well as unaffected controls (Renwick 2006, Tavtigian 2009, Decker 2017). Additionally, it has been reported in individuals with lung cancer, colon cancer, and at least one individual with a Lynch syndrome-associated cancer and/or colon polyps (Lu 2015, Yurgelun 2015, Pearlman 2017, Yurgelun 2017). ATM Thr935Met was observed at an allele frequency of 0.01% (13/126,690) in individuals of European 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Thr935Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204695 SCV000260536 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 935 of the ATM protein (p.Thr935Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs3218708, ExAC 0.02%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754) and individuals affected with colon cancer (PMID: 27978560, 28135145). It has also been reported in an individual affected with breast cancer and several control individuals (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 142503). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000204695 SCV000800392 uncertain significance Ataxia-telangiectasia syndrome 2018-06-04 criteria provided, single submitter clinical testing
Color RCV000131651 SCV000910760 likely benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780917 SCV000918568 uncertain significance not specified 2018-10-19 criteria provided, single submitter clinical testing Variant summary: ATM c.2804C>T (p.Thr935Met) results in a non-conservative amino acid change in 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 6.4e-05 in 282986 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (6.4e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.2804C>T, has been reported in the literature in individuals affected with colorectal cancer (Yurgelun_2015, Yurgelun_JAMAOnc_2016) but also in controls (Tavtigian_2009, Renwick_2006). These reports do not provide unequivocal conclusions about association of the variant with breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x3, likely benign x1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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