Submissions for variant NM_000051.4(ATM):c.1727T>C (p.Ile576Thr)

gnomAD frequency: 0.00011  dbSNP: rs730881342

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590025	SCV000209691	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing	Observed in a patient with breast cancer (Decker 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 21933854)
Ambry Genetics	RCV000159685	SCV000216297	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.I576T variant (also known as c.1727T>C), located in coding exon 10 of the ATM gene, results from a T to C substitution at nucleotide position 1727. The isoleucine at codon 576 is replaced by threonine, an amino acid with similar properties. This alteration was reported in 1/281 healthy controls and 0/318 individuals with chronic lymphocytic leukemia (CLL) in a study to determine the role of germline ATM mutations in the pathogenesis of CLL (Skowronska A et al. Haematologica. 2012 Jan;97:142-6) but was observed in 1/516 CLL patients and no controls in another study (Tiao G et al. Leukemia. 2017 10;31(10):2244-2247). This variant has also been reported in one patient diagnosed with breast cancer at age 50 from a cohort of 101 Norwegian breast and/or ovarian cancer patients (Jarhelle E et al. Sci Rep, 2019 12;9:19986) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000196810	SCV000254063	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 576 of the ATM protein (p.Ile576Thr). This variant is present in population databases (rs730881342, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 21933854, 28779002, 31882575). ClinVar contains an entry for this variant (Variation ID: 181920). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230420	SCV000694194	uncertain significance	not specified	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1727T>C (p.Ile576Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251712 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (9.1e-05 vs 0.001), allowing no conclusion about variant significance. c.1727T>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with Breast Cancer (example, Jarhelle_2019, Nurmi_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000159685	SCV000913551	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 576 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 31882575, 33471991, 36551643) and in unaffected controls (PMID: 21933854, 33471991, 36551643). In a large international case-control study, this variant was reported in 8/60458 breast cancer cases and 14/53447 controls (PMID: 33471991). This variant has been identified in 27/282550 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000196810	SCV002584710	uncertain significance	Ataxia-telangiectasia syndrome	2022-07-07	criteria provided, single submitter	clinical testing	The ATM c.1727T>C (p.Ile576Thr) missense change has a maximum frequency of 0.036% in gnomAD v2.1.1. 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. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 31882575). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). 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.
Athena Diagnostics	RCV000590025	SCV002771634	uncertain significance	not provided	2022-04-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003230420	SCV004027157	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462071	SCV004207032	uncertain significance	Familial cancer of breast	2023-10-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000196810	SCV001461012	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing