ClinVar Genomic variation as it relates to human health

This missense variant replaces alanine with aspartic acid at codon 2798 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant was observed in an individual affected with lung squamous cell carcinoma (PMID: 26689913) and a suspected hereditary breast cancer family with a pathogenic CTR9 canonical splice site variant (PMID: 31214250). This variant has been identified in 1/251158 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 sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2798 of the ATM protein (p.Ala2798Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with lung cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 220614). 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 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.

The p.A2798D variant (also known as c.8393C>A), located in coding exon 56 of the ATM gene, results from a C to A substitution at nucleotide position 8393. The alanine at codon 2798 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in a lung cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). This alteration was also detected on a 25-gene panel test in two women who were diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33) and in 1/10 families with BRCA1/2-negative familial breast cancer who underwent whole exome sequencing (Yin J et al. Front Genet, 2019 Jun;10:527).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.

Observed in individuals with a personal and/or family history of breast, ovarian, or lung cancer (PMID: 26689913, 25186627, 31214250, 34570441, 25905921); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25801821, 26689913, 25905921, 25186627, 31214250, 36243179, 23532176, 34570441)

. According to the ACMG standard criteria we chose this criterium: PM2 (supporting pathogenic): 1X in gnomAD NFE

Variant summary: ATM c.8393C>A (p.Ala2798Asp) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain 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-06 in 251158 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8393C>A has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (Tung_2015, Okawa_2023, Yin_2019, Dong_2022). These report(s) 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. ClinVar contains an entry for this variant (Variation ID: 220614). Based on the evidence outlined above, the variant was classified as uncertain significance.

Variant interpreted as Uncertain significance and reported on 09-10-2020 by Lab or GTR ID 239772. 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.