ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3371A>T (p.Tyr1124Phe) (rs876660498)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223446 SCV000277977 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000590071 SCV000564628 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.3371A>T at the cDNA level, p.Tyr1124Phe (Y1124F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAC>TTC). This variant was observed in a pediatric patient with hypodiploid acute lymphocytic leukemia (Zhang 2015). ATM Tyr1124Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr1124Phe occurs at a position that is not conserved and is located within the region of interaction with beta-adaptin (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Tyr1124Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000538570 SCV000622415 uncertain significance Ataxia-telangiectasia syndrome 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 1124 of the ATM protein (p.Tyr1124Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with acute myeloid leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 233576). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
Color RCV000223446 SCV000682123 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590071 SCV000694257 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.3371A>T (p.Tyr1124Phe) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120570 control chromosomes and has been reported in the literature in one ALL patient, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
Fulgent Genetics,Fulgent Genetics RCV000763698 SCV000894578 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Center of Medical Genetics and Primary Health Care RCV000223446 SCV000987259 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-08 no assertion criteria provided research This variant is in exon 18 in a non-functional domain. The Tyr1124 residue is the first codon of exon 18 just before the LZ functional domain, which plays a role in DNA damage repair. This missense variant is in a hotspot of 8 pathogenic variants (PM1 Pathogenic Moderate). The allele frequencies in GnomAD exomes and GnomAD genomes are 0.000012 and 0.0001, respectively, which are less the threshold 0.0001 for recessive gene ATM (PM2 Pathogenic Moderate). 8 benign predictions from Align-GVGD, DANN, DEOGEN2, EIGEN, MVP, MutationTaster, PrimateAI and REVEL versus 4 pathogenic predictions from FATHMM-MKL, M-CAP, MutationAssessor support its benign effect (BP4 Benign Supporting). This variant has been observed in an individual affected with acute myeloid leukemia (PMID: 26580448). This variant is reported in ClinVar as a VUS. In our study this variant was found in a 26-year-old female with unilateral breast cancer and a strong family history of cancer. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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