ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27498913, 27443514, 26010451, 27978560, 29356034, 29058119, 27304073, 24983367, 33280026, 32832836, 31617914, Carpenter2024[computational], 23532176)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: ATM c.7381C>T (p.Arg2461Cys) 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 8.4e-05 in 251274 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.4e-05 vs 0.004), allowing no conclusion about variant significance. c.7381C>T has been reported as a VUS in the literature in individuals undergoing hereditary cancer panel testing for a variety of cancer indications (example, Ring_2016, Pearlman_2017, Feliubadalo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/breast cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.2744_2745delCT, p.Ser915*), providing supporting evidence for a benign role in relationship to breast cancer but not Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

The ATM c.7381C>T variant is predicted to result in the amino acid substitution p.Arg2461Cys. This variant has been reported in individuals with endometrial, colorectal, and prostate cancer (Ring et al. 2016. PubMed ID: 27443514, Table S2; Pearlman et al. 2017. PubMed ID: 27978560, eTable 2; Beebe-Dimmer et al. 2018. PubMed ID: 29356034). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108201014-C-T) and is interpreted as uncertain significance by the vast majority of clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142541/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The p.R2461C variant (also known as c.7381C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7381. The arginine at codon 2461 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was previously reported in two individuals who underwent multi-gene panel testing and was classified as a variant of unknown significance. One individual was diagnosed with endometrial cancer and the other with early-onset colorectal cancer (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-9; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This alteration was also reported in the heterozygous state in a Caucasian male meeting Chompret criteria who was diagnosed with spindle cell sarcoma of the liver at age 42 years (Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71). In addition, this alteration was also observed in individuals diagnosed with prostate cancer (Beebe-Dimmer JL et al. Prostate, 2018 04;78:321-326; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

The c.7381C>T (p.Arg2461Cys) variant has an allele frequency of 0.000093 (0.009%, 25/268,148 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00064 (0.06%, 15/23,620 alleles) in the Afican subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor. A cryptic acceptor site is activated according to SpliceSiteFinderlike and MaxEnt, but its score slightly exceeds the natural one only according to SpliceSiteFinderlike and no splicing site is created/activated according to NNSplice and GeneSplicer. However, missense variant alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 (PMID: 33280026).

This missense variant replaces arginine with cysteine at codon 2461 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. In a large international case-control study, this variant was reported in 6/60466 breast cancer cases and 3/53461 controls (OR=1.768, 95%CI 0.442 to 7.071, p-value=0.515; PMID: 33471991). This variant has also been reported in individuals affected with early-onset or bilateral breast cancer (Color internal data), early-onset prostate cancer (PMID: 29356034), colorectal cancer (PMID: 28135145, 27978560), sarcoma (PMID: 27498913), and endometrial carcinoma (PMID: 27443514). This variant has been identified in 26/282686 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.

Variant interpreted as Likely benign and reported on 01-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.