ClinVar Genomic variation as it relates to human health

The ATM c.8428A>C; p.Lys2810Gln variant (rs730881325) is reported in an individual with early-onset colorectal cancer (de Voer 2016), and an individual with a hereditary cancer syndrome (Tsaousis 2019); however, it is also found in healthy controls (Tiao 2017). This variant is reported in ClinVar (Variation ID: 181898). It is found in the general population with an overall allele frequency of 0.004% (11/281884 alleles) in the Genome Aggregation Database. The lysine at codon 2810 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES de Voer RM et al. Identification of Novel Candidate Genes for Early-Onset Colorectal Cancer Susceptibility. PLoS Genet. 2016 Feb 22;12(2):e1005880. Tiao G et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017 Oct;31(10):2244-2247. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535.

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2810 of the ATM protein (p.Lys2810Gln). This variant is present in population databases (rs730881325, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal and prostate cancer and/or individual(s) undergoing genetic testing for hereditary cancer (PMID: 26901136, 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 181898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

This missense variant replaces lysine with glutamine at codon 2810 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. This variant has been reported in individuals affected with colorectal, prostate, pancreatic, or breast cancer (PMID: 26901136, 28726808, 29522266, 33436325, 33471991; https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4012663). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has also been identified in 11/281884 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, or prostate cancer as well as in an infant with rhabdomyosarcoma (PMID: 26901136, 29522266, 34067464, 33436325); This variant is associated with the following publications: (PMID: 26901136, 28652578, 29522266, 31159747, 33436325, 33875564, 34067464, 23532176, 35451682)

Variant summary: ATM c.8428A>C (p.Lys2810Gln) results in a conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250508 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.8428A>C has been reported in the literature in individuals undergoing multigene panel testing for hereditary cancers (example, Tsaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. 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: 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 181898). Based on the evidence outlined above, the variant was classified as uncertain significance.

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 ATM p.Lys2810Gln variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs730881325) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae, Ambry Genetics and Color Genomics Inc.), Clinvitae (4x), and in control databases in 11 of 276512 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 7 of 126486 chromosomes (freq: 0.00006), European Finnish in 4 of 25756 chromosomes (freq: 0.0002), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Lys2810Gln is located in the phosphatidylinositol 3-/4-kinase, catalytic domain and may have clinical significance. The p.Lys2810 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Gln impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.