Submissions for variant NM_000051.4(ATM):c.7996A>G (p.Thr2666Ala)

gnomAD frequency: 0.00001  dbSNP: rs745775382

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205336	SCV000259552	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2666 of the ATM protein (p.Thr2666Ala). This variant is present in population databases (rs745775382, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 219594). 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 disruptive. This variant disrupts the p.Thr2666 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26633542; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000222128	SCV000277848	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-09	criteria provided, single submitter	clinical testing	The p.T2666A variant (also known as c.7996A>G), located in coding exon 53 of the ATM gene, results from an A to G substitution at nucleotide position 7996. The threonine at codon 2666 is replaced by alanine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 1 in 7051 un-selected breast cancer patients and 0 in 11241 female controls of Japanese ancestry. 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.
Color Diagnostics, LLC DBA Color Health	RCV000222128	SCV001339707	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2666 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 30287823) and a healthy control (PMID: 33471991). This variant has been identified in 2/251092 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	RCV001193061	SCV001361641	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7996A>G (p.Thr2666Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 280173 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7996A>G has been reported in the literature in individuals affected with breast cancer (e.g. Park_2015, Momozawa_2018), lung cancer (e.g. Davies_2005), and CLL (e.g. Navrkalova_2013) without strong evidence for causality due to absence of co-segregation. To our knowledge, c.7996A>G has not been reported in the literature in individuals affected with Ataxia-Telangiectasia. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or any of the solid tumors ascertained. At least three publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Navrkalova_2013, Riabinska_2013, Weber_2016). The following publications have been ascertained in the context of this evaluation (PMID: 16140923, 23836671, 17344846, 25925381, 30287823, 23585524, 26009992, 23761041, 29415044, 28652578, 25523272, 22585170, 27602502). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3; LP, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356715	SCV001551957	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr2666Ala variant was identified in 3 of 14382 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or chronic lymphocytic leukemia and was not identified in 22482 control chromosomes from healthy individuals (Momozawa 2018, Navrkalova 2013). The variant was also identified in dbSNP (ID: rs745775382) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae and Ambry Genetics), and in LOVD 3.0 (1x as uncertain significance). The variant was identified in 2 of 245914 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 2 of 111422 chromosomes (freq: 0.00002), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Thr2666 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.