Submissions for variant NM_000051.4(ATM):c.3059C>T (p.Thr1020Ile)

dbSNP: rs186626274

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204390	SCV000260339	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1020 of the ATM protein (p.Thr1020Ile). This variant is present in population databases (rs186626274, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 220080). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000220730	SCV000275217	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	clinical testing	The p.T1020I variant (also known as c.3059C>T), located in coding exon 19 of the ATM gene, results from a C to T substitution at nucleotide position 3059. The threonine at codon 1020 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00043 in 7051 unselected breast cancer patients and 0.00036 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000587502	SCV000564625	uncertain significance	not provided	2024-02-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer as well as unaffected controls (PMID: 30287823, 26822949, 33471991, 32885271); This variant is associated with the following publications: (PMID: 30287823, 26822949, 27499925, 29685880, 33875564, 33471991, 19781682, 32885271, 36243179)
Color Diagnostics, LLC DBA Color Health	RCV000220730	SCV000682099	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1020 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in healthy controls (PMID: 26822949, 33471991). This variant has been identified in 3/250920 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587502	SCV000694247	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.3059C>T (p.Thr1020Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. This variant is located in the Armadillo-type fold (IPR016024) (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 1/120648 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was reported in one patient without co-occurrence or co-segregation data. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Due to the paucity of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000204390	SCV001440810	uncertain significance	Ataxia-telangiectasia syndrome	2019-01-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288828	SCV002579690	uncertain significance	Familial cancer of breast	2022-02-10	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000204390	SCV002584754	uncertain significance	Ataxia-telangiectasia syndrome	2022-07-20	criteria provided, single submitter	clinical testing	The ATM c.3059C>T (p.Thr1020Ile) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. A small case-control study of females with breast cancer indicates that this variant does not have an increased prevalence in cases versus controls (P value = 1.00, OR = 1.2, 95% CI: 0.2-7.1; PMID: 30287823). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV002288828	SCV004208263	uncertain significance	Familial cancer of breast	2024-02-25	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357524	SCV001553021	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr1020Ile variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in dbSNP (ID: rs186626274) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx), Clinvitae (classified as uncertain significance by ClinVar, Invitae), databases. The variant was identified in control databases in 3 of 245678 chromosomes at a frequency of 0.000012 (Genome Aggregation Consortium Feb 27, 2017). The p.Thr1020 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. This variant is located within the Armadillo-type Fold unctional domain, increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000204390	SCV002076614	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-17	no assertion criteria provided	clinical testing