Submissions for variant NM_000051.4(ATM):c.290T>C (p.Ile97Thr)

gnomAD frequency: 0.00007  dbSNP: rs786203011

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166129	SCV000216900	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	The p.I97T variant (also known as c.290T>C), located in coding exon 3 of the ATM gene, results from a T to C substitution at nucleotide position 290. The isoleucine at codon 97 is replaced by threonine, an amino acid with similar properties.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.
Invitae	RCV000200635	SCV000254076	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	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 97 of the ATM protein (p.Ile97Thr). This variant is present in population databases (rs786203011, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 186520). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000585916	SCV000292825	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with Lynch-related cancer or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 19781682, 23532176, 25980754)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804170	SCV000694226	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.290T>C (p.Ile97Thr) results in a non-conservative amino acid change located in the telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 150724 control chromosomes, predominantly at a frequency of 0.0002 (i.e. 8 / 41086 alleles) within the African or African-American subpopulation in the gnomAD database (v3.1 genomes dataset). The variant has also been reported in 1 / 2559 African American women, who are older than age 70 and cancer free (FLOSSIES database). The available data on variant occurrences in the general population are insufficient to allow clear conclusion about variant significance. The variant, c.290T>C, has been reported in the literature in an individual affected with Lynch syndrome-associated cancer and/or polyps (Yurgelun_2015). 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Eurofins Ntd Llc (ga)	RCV000585916	SCV000702266	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767895	SCV000898526	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-03-30	criteria provided, single submitter	clinical testing	ATM NM_000051.3 exon 4 p.Ile97Thr (c.290T>C): This variant has been reported in the literature in 1 individual with a clinical suspicion of Lynch syndrome (Yurgelun 2015 PMID:25980754). This variant is present in 5/24000 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs786203011). This variant is present in ClinVar with several entries as "Variant of Uncertain Significance" (Variation ID:186520). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000166129	SCV000906532	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 97 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 an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 5/282288 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.
Athena Diagnostics	RCV000585916	SCV002771771	uncertain significance	not provided	2021-12-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004552916	SCV004109235	uncertain significance	ATM-related disorder	2023-08-07	criteria provided, single submitter	clinical testing	The ATM c.290T>C variant is predicted to result in the amino acid substitution p.Ile97Thr. This variant has been reported in an individual undergoing Lynch syndrome hereditary cancer testing (Table S2. Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108100009-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/186520/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003468773	SCV004208141	uncertain significance	Familial cancer of breast	2024-02-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000200635	SCV002088366	uncertain significance	Ataxia-telangiectasia syndrome	2020-12-18	no assertion criteria provided	clinical testing