ClinVar Genomic variation as it relates to human health

This missense variant replaces leucine with phenylalanine at codon 950 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 performed for this variant. The variant has been reported in an individual affected with colorectal cancer (PMID: 28640387). This variant has been identified in 13/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant affecting the same codon, p.Leu950Arg, is considered to be disease-causing (ClinVar Variation ID: 186574), suggesting that leucine at this position is important for ATM protein function. The available evidence for the p.Leu950Phe variant is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 950 of the ATM protein (p.Leu950Phe). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs763064034, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This missense change has been observed to co-occur in individuals with a different variant in ATM that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 220494). 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. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 19 (Invitae). This variant disrupts the p.Leu950 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10873394, 12552559, 20678261, 21792198). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Variant summary: The variant, ATM c.2848C>T (p.Leu950Phe) 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 5.1e-05 in 277140 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.00038 in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00038 vs. 0.001), allowing no conclusion about variant significance. The variant, c.2848C>T has been reported in the literature in an individual affected with colorectal cancer (Ricker 2017). However, 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. A different missense change affecting the same amino acid residue (c.2849T>G, p.Leu950Arg) is reported in ClinVar as likely pathogenic that might indicate the importance of this amino acid residue in protein function. The following publication have been ascertained in the context of this evaluation (PMID: 28640387). ClinVar contains an entry for this variant (Variation ID: 220494). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.L950F variant (also known as c.2848C>T), located in coding exon 18 of the ATM gene, results from a C to T substitution at nucleotide position 2848. The leucine at codon 950 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with colorectal cancer at 48 (Ricker CN et al. Cancer, 2017 Oct;123:3732-3743). RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This amino acid position is highly 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.

A different missense change at this residue (p.L950R) has been reported as likely pathogenic at GeneDx; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 28640387)

The ATM c.2848C>T variant is predicted to result in the amino acid substitution p.Leu950Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD and listed as a variant of uncertain significance (VUS) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/220494/). Of note, a different substitution at the same codon, defined as c.2849T>G (p.Leu950Arg), was identified in individuals with ataxia telangiectasia or prostate cancer (see for example, reported as L949R at Becker-Catania et al. 2000. PubMed ID: 10873394; Na et al. 2017. PubMed ID: 27989354); and this variant is listed as likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/186574/). At this time, the clinical significance of the c.2848C>T (p.Leu950Phe) variant is uncertain due to the absence of conclusive functional and genetic evidence.