ClinVar Genomic variation as it relates to human health

The c.3295G>A (p.Asp1099Asn) sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Asn). This variant is present in population databases (rs372966951, gnomAD 0.02%). This missense change has been observed in individuals with breast, colorectal, and other cancers (PMID: 19781682, 28135145, 30455982, 30093976); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976, 26976419) . ClinVar contains an entry for this variant (Variation ID: 188196).In silico analysis supports that this missense variant does not alter protein structure/function. 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: ATM c.3295G>A (p.Asp1099Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3295G>A has been reported in the literature in individuals affected with Breast Cancer, Lymphoma, Mullerian Adenocarcinoma, Colorectal cancer and Pediatric cancer predisposition syndrome without evidence for causality (example, Fang_2003, Tavtigian_2009, Goldgar_2011, Howitt_2015, Yurgelun_2017, Tung_2016, Young_2015, Chan_Oncotarget_2018, Chan_Genomic Med_2018). 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. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has classified the variant as likely benign and four others have classified it as variant of unknown significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, and other cancers (PMID: 19781682, 28135145, 30455982, 30093976); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976, 26976419)

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Asn). This variant is present in population databases (rs372966951, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 19781682, 21787400, 28135145, 30093976). ClinVar contains an entry for this variant (Variation ID: 188196). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.D1099N variant (also known as c.3295G>A), located in coding exon 22 of the ATM gene, results from a G to A substitution at nucleotide position 3295. The aspartic acid at codon 1099 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple breast cancer patients (Tavtigian SV et al. Am. J. Hum. Genet., 2009 Oct;85:427-46; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The ATM p.Asp1099Asn variant was identified in 4 of 15480 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and colorectal cancer and was not identified in 7694 control chromosomes from healthy individuals (Tavtigian 2009, Goldgar 2011, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs372966951) as "With Uncertain significance allele", and in ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Integrated Genetics). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 7 of 239322 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5374 chromosomes (freq: 0.0002), and South Asian in 6 of 30298 chromosomes (freq: 0.0002); it was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Asp1099 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

The ATM c.3295G>A variant is predicted to result in the amino acid substitution p.Asp1099Asn. This variant has been reported in patients with breast or colorectal cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S2, Chan et al. 2018. PubMed ID: 30093976). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD and is listed in ClinVar with conflicting interpretation of likely benign (1) and uncertain (7) (https://www.ncbi.nlm.nih.gov/clinvar/variation/188196/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.