ClinVar Genomic variation as it relates to human health

The p.L2492R variant (also known as c.7475T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide position 7475. The leucine at codon 2492 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in multiple cohorts of individuals referred for genetic testing (Lu C et al. Nat Commun. 2015 Dec;6:10086; Tiao G et al. Leukemia. 2017 10;31:2244-2247; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). 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.

The ATM c.7475T>G; p.Leu2492Arg variant (rs56399857) is reported in the literature in individuals with colorectal cancer (Yurgelun 2017), chronic lymphocytic leukemia (Tiao 2017), and glioblastoma multiforme (Lu 2015). This variant is reported with uncertain significance by multiple laboratories in ClinVar (Variation ID: 127446). It is found in the general population with an overall allele frequency of 0.01% (32/282684 alleles) in the Genome Aggregation Database. The leucine at codon 2492 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Tiao G et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017 Oct;31(10):2244-2247. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095.

In the published literature, this variant has been reported in a control individual and in individuals affected with breast cancer (PMID: 30306255 (2018), 28779002 (2017), 20305132 (2010)), ovarian cancer (PMID: 30441849 (2018)), lung adenocarcinoma (PMID: 17344846 (2007)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), glioblastoma (PMID: 26689913 (2015)), prostate cancer (PMID: 32606146 (2020)), and Lynch syndrome-associated cancer and/or polyps (PMID: 28135145 (2017), 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.00039 (13/33062 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: ATM c.7475T>G (p.Leu2492Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) 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 9.9e-05 in 251282 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (9.9e-05 vs 0.001), allowing no conclusion about variant significance. c.7475T>G has been reported in the literature primarily as a VUS in settings of multigene panel testing in individuals affected with breast, prostate, and other cancers and also in healthy controls (e.g. Bernstein_2010, Greenman_2007, Lu_2015, Tiao_2017, Young_2016, Yurgelun_2015, Yurgelun_2017, Bonache_2018, Tsaousis_2019, Holeckova_2020, Krivokuca_2022, Paduano_2022). In addition, the variant was found in 5/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 30306255, 17344846, 32606146, 34284872, 26689913, 35886069, 28652578, 31159747, 26787654, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 127446). Based on the evidence outlined above, the variant was classified as uncertain significance.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, colon, and other cancers (PMID: 17344846, 26689913, 28779002, 28652578, 28135145, 30306255, 29522266, 30441849, 29684080, 32606146, 35347810, 35886069, 35127508, 36029002); Present at similar frequency among breast cancer cases and controls in a large case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 35347810, 35127508, 35886069, 22529920, 17344846, 26689913, 25980754, 26787654, 22173549, 28873162, 28135145, 28652578, 26206375, 29522266, 28779002, 29684080, 30306255, 31159747, 31422574, 20305132, 30441849, 31920950, 32606146, 35047863, 36011273, 34284872, 23532176, 34718612, 33471991, 34262154, 35980532, 36029002, 37351993)

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.7475T>G, in exon 50 that results in an amino acid change, p.Leu2492Arg. This sequence change has been described in the gnomAD database with a frequency of 0.024% in the European (Non-Finnish) subpopulation (dbSNP rs56399857). The p.Leu2492Arg change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Leu2492Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously identified in individuals who have undergone hereditary cancer genetic testing (PMID: 31159747, 25980754) and in an individual with a history of unilateral breast cancer (PMID: 20305132) and in an individual with a history colon cancer (28135145). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu2492Arg change remains unknown at this time.

The ATM c.7475T>G (p.Leu2492Arg) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with many cancer types including breast, colorectal, prostate, pancreatic, and chronic lymphocytic leukemia (PMID: 28135145, 28652578, 30306255, 32606146, 35047863). This variant has been reported in 5 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. 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.

ATM: PM2

The ATM c.7475T>G variant is predicted to result in the amino acid substitution p.Leu2492Arg. This variant has been reported in individuals with breast cancer, ovarian cancer, chronic lymphocytic leukemia, colorectal cancer, lynch syndrome, and glioblastoma multiforme (Table S1, Bernstein et al. 2010. PubMed ID: 20305132; Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S12, Lu et al. 2015. PubMed ID: 26689913Table S5, Decker et al. Decker et al. 2017. PubMed ID: 28779002; Table S3, Tiao et al. 2017. PubMed ID: 28652578; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table 2, Bonache et al. 2018. PubMed ID: 30306255; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849; Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance by the vast majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/127446/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This variant is denoted ATM c.7475T>G at the cDNA level, p.Leu2492Arg at the protein level, and is a non-conservative amino acid change located in the PIK-related kinase, FAT domain (Stracker 2013) of the encoded protein sequence. Five of five in silico tools predict a damaging effect of this variant on protein function. This is a rare variant (ExAC 0.00006), and has been reported in various cancers (Lu 2015, Greenman 2007, Berstein 2010). We report this variant to occur in two sisters, both heterozygotes, with breast cancer, of 47 and 50 years old. The second one also developed thyroid cancer at the age of 55. A third sister tested, is a healthy non-carrier at the age of 59 years old. The family on the paternal side included one case of breast cancer at the age of 70 years old, and another one with breast and thyroid cancer at the age of 40 and 65 years old respectively. For these reasons, this variant may be causative of disease in this family and we classify it as probably pathogenic.