Submissions for variant NM_000051.4(ATM):c.4673C>T (p.Thr1558Met)

gnomAD frequency: 0.00004  dbSNP: rs587781712

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129888	SCV000184705	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.T1558M variant (also known as c.4673C>T), located in coding exon 30 of the ATM gene, results from a C to T substitution at nucleotide position 4673. The threonine at codon 1558 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in individuals from cancer cohorts and in unaffected control populations in several case-control studies (Tiao G et al. Leukemia, 2017 Oct;31:2244-2247; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Dorling et al. N Engl J Med 2021 02;384:428-439; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration was also reported along with another ATM missense alteration in a patient with ataxia telangiectasia (Woelke S et al. Front Immunol 2018 Sep;9:2000). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212020	SCV000209739	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a second ATM variant in an individual with ataxia-telangiectasia (Woelke et al., 2018); This variant is associated with the following publications: (PMID: 26022708, 30287823, 28652578, 30279689, 33436325)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542530	SCV000622522	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1558 of the ATM protein (p.Thr1558Met). This variant is present in population databases (rs587781712, gnomAD 0.02%). This missense change has been observed in individual(s) with gastric cancer and/or prostate cancer (PMID: 33436325, 34326862). ClinVar contains an entry for this variant (Variation ID: 141389). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763704	SCV000894584	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129888	SCV000903256	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1558 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. In prostate and breast cancer case-control studies, this variant has been observed in affected and unaffected individuals (PMID: 30287823, 33436325, 33471991). In a biliary tract cancer case-control study, the variant was not observed in affected cases and present in the control group (PMID: 36243179). This variant has been observed in an individual affected with gastric cancer who has a family history of gastric cancer (PMID: 34326862). This variant has been identified in 6/281966 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	RCV002222401	SCV002500146	uncertain significance	not specified	2023-09-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4673C>T (p.Thr1558Met) 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 2e-05 in 250606 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4673C>T has been reported, in case-control studies or in case reports, in individuals affected with Ataxia-Telangiectasia and various types of cancers including Breast cancer, Gastric cancer, biliary tract cancer, and prostate cancer (example, Karlsson_2021, Momozawa_2018, Tiao_2017, Woelke_2018, Dorling_2021, Bhai_2021, Okawa_2023), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33436325, 30287823, 28652578, 30279689, 33471991, 34326862, 36243179). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315232	SCV004012955	uncertain significance	Diffuse midline glioma, H3 K27-altered	2021-08-05	criteria provided, single submitter	research
Baylor Genetics	RCV003467125	SCV004209430	uncertain significance	Familial cancer of breast	2024-02-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000542530	SCV001462336	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551250	SCV004710492	uncertain significance	ATM-related disorder	2024-08-12	no assertion criteria provided	clinical testing	The ATM c.4673C>T variant is predicted to result in the amino acid substitution p.Thr1558Met. This variant has been reported in an individual with prostate cancer and interpreted as uncertain significance (Karlsson et al. 2021. PubMed ID: 33436325, Table S4). It has also been reported in controls from a breast cancer cohort study  (Momozawa et al. 2018. PubMed ID: 30287823, Table S1). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141389/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.