Submissions for variant NM_000051.4(ATM):c.7570G>C (p.Ala2524Pro)

gnomAD frequency: 0.00001  dbSNP: rs769142993

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167357	SCV000218209	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.A2524P variant (also known as c.7570G>C), located in coding exon 50 of the ATM gene, results from a G to C substitution at nucleotide position 7570. The alanine at codon 2524 is replaced by proline, an amino acid with highly similar properties. This alteration was observed in two Finnish ataxia telangiectasia (AT) families (Allinen M et al. J Med Genet. 2002 Mar;39(3):192-6). This alteration has also been observed as heterozygous in multiple individuals diagnosed with breast or prostate cancer (Allinen M et al. J Med Genet. 2002 Mar;39(3):192-6; Bubien V et al. Genes Chromosomes Cancer. 2017 Nov;56(11):788-799; Nurmi A et al. Int. J. Cancer, 2019 11;145:2692-2700; Rantapero T et al. Genes (Basel), 2020 03;11:; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). One functional study demonstrated that this alteration leads to a stable protein that is defective in kinase activity (Pylkas K et al. Carcinogenesis. 2007 May;28(5):1040-5). A second functional study demonstrated that this alteration leads to a significantly decreased response to ionizing radiation that is similar to that of a control AT cell line (Jacquemin V et al. Eur J Hum Genet. 2012 Mar;20(3):305-12). One meta-analysis provided a rough estimate that this alteration may confer a 7-fold increased risk for breast cancer over the general population (Hollestelle A et al. Curr Opin Genet Dev. 2010 Jun;20(3):268-76). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550379	SCV000622760	pathogenic	Ataxia-telangiectasia syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2524 of the ATM protein (p.Ala2524Pro). This variant is present in population databases (rs769142993, gnomAD 0.03%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or ATM-related cancers (PMID: 10980530, 11897822, 16622469). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 187613). 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 have shown that this missense change affects ATM function (PMID: 17166884, 22071889). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003319326	SCV004023460	pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing	Observed in the compound heterozygous or homozygous state in multiple unrelated patients with ataxia-telangiectasia, and confirmed to be on the opposite allele (in trans) with a pathogenic variant in at least one individual (PMID: 10980530, 11897822, 22071889); Published functional studies suggest a damaging effect: defective kinase activity (PMID: 17166884, 22071889); 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: 16622469, 16914028, 30927251, 32853339, 35095854, 33436325, 32183364, 29922827, 36467798, 20346647, 11897822, 10980530, 19224889, 22071889, 17166884, 23532176, 36551643, 36161273, 37578974)