ClinVar Genomic variation as it relates to human health

Variant summary: ATM c.7235A>G (p.Asn2412Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7235A>G has been reported in the literature as a VUS in individuals undergoing multigene panel testing for colorectal/breast cancer (example, Yurgelun_2017, Tsaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.N2412S variant (also known as c.7235A>G), located in coding exon 48 of the ATM gene, results from an A to G substitution at nucleotide position 7235. The asparagine at codon 2412 is replaced by serine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Nunziato M et al. Anal Chim Acta, 2019 Jan;1046:154-162; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This alteration has also been reported in 2/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This variant has also been reported in an individual diagnosed with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). 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.

Observed in individuals with a personal and/or family history of colorectal, breast, and/or ovarian cancer (Yurgelun 2017, Hauke 2018, Nunziato 2019, Tsaousis 2019).; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135145, 29522266, 31159747, 30482293)

ATM: PM2

This missense variant replaces asparagine with serine at codon 2412 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 reported for this variant. In a large international case-control study, this variant was reported in 0/60466 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been reported in individuals affected with breast cancer and colorectal cancer (PMID: 28135145, 30482293). This variant has also been identified in 1/251290 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.