Submissions for variant NM_000051.4(ATM):c.7468C>T (p.Leu2490Phe)

gnomAD frequency: 0.00001  dbSNP: rs753262623

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219162	SCV000273256	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-09	criteria provided, single submitter	clinical testing	The p.L2490F variant (also known as c.7468C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7468. The leucine at codon 2490 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in a male diagnosed with breast cancer (Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229441	SCV000283056	uncertain significance	Ataxia-telangiectasia syndrome	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2490 of the ATM protein (p.Leu2490Phe). This variant is present in population databases (rs753262623, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or lung adenocarcinoma (PMID: 26689913, 30613976, 32365829). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 229889). 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. 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	RCV000587941	SCV000293273	uncertain significance	not provided	2019-12-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with lung cancer (Lu 2015); This variant is associated with the following publications: (PMID: 25320358, 26689913)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420712	SCV000694353	uncertain significance	not specified	2021-05-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7468C>T (p.Leu2490Phe) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of 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 8e-06 in 251294 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7468C>T has been reported in the literature in individuals affected with lung adenocarcinoma and male breast cancer (example: Parry_2017, Lu_2015, Rizzolo_2019). Several somatic occurrences of this variant has also been reported in the literature (example: Damm_2014). These reports however, do 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. Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000219162	SCV000904731	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-03	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 2490 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lung adenocarcinoma (PMID: 26689913). This variant has also been identified in 2/251294 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587941	SCV002010784	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003765399	SCV004611135	uncertain significance	Familial cancer of breast	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2490 of the ATM protein (p.Leu2490Phe). This variant is present in population databases (rs753262623, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or lung adenocarcinoma (PMID: 26689913, 30613976, 32365829). ClinVar contains an entry for this variant (Variation ID: 229889). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. Heterozygous pathogenic/likely pathogenic variants in the ATM gene cause familial susceptibility to breast cancer (OMIM 114480).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587941	SCV005626260	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing