ATM NM_000051.4:c.4049C>T, Thr1350Met

Variant summary: ATM c.4049C>T (p.Thr1350Met) results in a non-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 5.2e-05 in 271256 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.2e-05 vs 0.004), allowing no conclusion about variant significance. c.4049C>T has been reported in the literature in at least one individual affected with familial cutaneous melanoma (e.g. Pastorino_2020), and in individuals with breast cancer as well as healthy control subjects (Momozawa_2018, Kwong_2020, Dorling_2021). These reports 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: 30287823, 30181556, 32325837, 28119368, 33471991, 32068069). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces threonine with methionine at codon 1350 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. This variant has been reported in an individual affected with cutaneous melanoma (PMID: 32325837). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). This variant has also been identified in 13/248774 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.

The p.T1350M variant (also known as c.4049C>T), located in coding exon 26 of the ATM gene, results from a C to T substitution at nucleotide position 4049. The threonine at codon 1350 is replaced by methionine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.