ClinVar Genomic variation as it relates to human health

Variant summary: ATM c.7463G>A (p.Cys2488Tyr) 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 8e-06 in 251500 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature, primarily in settings of multigene panel testing, in individuals affected with CLL wherein some cases likely have been reported in multiple publications (e.g. Navrkalova_2013, Sutton_2015, te Raa_2015, Spunarova_2019, Tausch_2020, Petrackova_2022, Lampson_2023), in individuals with breast and/or ovarian cancer (e.g. Lhota_2016, Lu_2018), in at least one individual with prostate cancer (e.g. Brady_2022) and in individuals with various other cancer types (e.g. Susswein_2015, Hu_2018, Zhang_2023), all without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with breast or prostate cancer. At least two publications report experimental evidence evaluating an impact on protein function(e.g. Navrkalova_2013, te Raa_2015), however, none of these studies allows convincing conclusions about the variant effect. The variant was reported to not affect protein expression, but diminish autophosphorylation function, though primary evidence was not provided for independent evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 35467778, 29922827, 36315919, 26822949, 30128536, 23585524, 36029002, 32183364, 31054420, 26681312, 25480502, 31919090, 19781682, 12810666, 36627197, 26247737). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and two classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2488 of the ATM protein (p.Cys2488Tyr). This variant is present in population databases (rs774281788, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and chronic lymphocytic leukemia (PMID: 23585524, 26681312, 29922827, 30128536). ClinVar contains an entry for this variant (Variation ID: 187037). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 23585524). 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.

The p.C2488Y variant (also known as c.7463G>A), located in coding exon 49 of the ATM gene, results from a G to A substitution at nucleotide position 7463. The cysteine at codon is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature in the germline of a CLL patient; functional assessment of this alteration revealed a normal level of ATM protein, but the protein was reported as defective (Navrkalova V et al, Haematologica 2013 Jul; 98(7):1124-31). This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). A different nucleotide change resulting in the same amino acid change, p.C2488Y (c.7463G>T), has also been reported in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This amino acid position is highly conserved through mammals, but poorly conserved in reptiles and fish. 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.

According to the ClinGen ACMG ATM v1.1.0 criteria we chose this criterion: PP3 (supporting pathogenic): REVEL 0.883

This missense variant replaces cysteine with tyrosine at codon 2488 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). Experimental studies have indicated this protein variant may have an impact on ATM function (PMID: 23585524, 22071889, 36029002). This protein variant has been reported in individuals affected with breast cancer (PMID: 12810666, 19781682, 26822949, 33471991) and chronic lymphocytic leukemia (CLL; PMID: 23585524, 25480502, 26247737, 36029002) in the literature. This variant has been identified in 2/251290 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.

Observed in individuals with a personal history of chronic lymphocytic leukemia, pancreatic, breast and/or ovarian cancer (PMID: 12810666, 19781682, 23585524, 29522266, 29922827); Published functional studies are inconclusive: no effect on protein levels but results in impaired protein function (PMID: 23585524); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26681312, 27479817, 12810666, 19781682, 25480502, 29922827, 30128536, 26822949, 26247737, 22071889, 36029002, 32183364, 29522266, 31054420, 23532176, 23585524)

Variant interpreted as Likely pathogenic and reported on 03-04-2017 by GeneDx. 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.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.