ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2848C>T (p.Leu950Phe) (rs763064034)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204174 SCV000261078 uncertain significance Ataxia-telangiectasia syndrome 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 950 of the ATM protein (p.Leu950Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs763064034, ExAC 0.009%). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 220494). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu950 amino acid residue in ATM. Other variant(s) that disrupt this residue have been observed in individuals with ATM-related conditions (PMID: 10873394, 20678261, 12552559, 21792198, 20678261, 10873394), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Ambry Genetics RCV000219592 SCV000277209 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000589680 SCV000293196 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.2848C>T at the cDNA level, p.Leu950Phe (L950F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has been reported in a Latino individual with colorectal cancer (Ricker 2017). ATM Leu950Phe was observed at an allele frequency of 0.04% (13/34414) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Leu950Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000219592 SCV000682084 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855572 SCV000694237 uncertain significance not specified 2019-03-07 criteria provided, single submitter clinical testing Variant summary: The variant, ATM c.2848C>T (p.Leu950Phe) 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 5.1e-05 in 277140 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.00038 in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00038 vs. 0.001), allowing no conclusion about variant significance. The variant, c.2848C>T has been reported in the literature in an individual affected with colorectal cancer (Ricker 2017). However, this report does 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. A different missense change affecting the same amino acid residue (c.2849T>G, p.Leu950Arg) is reported in ClinVar as likely pathogenic that might indicate the importance of this amino acid residue in protein function. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000763693 SCV000894573 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing

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