Submissions for variant NM_000051.4(ATM):c.7926A>C (p.Arg2642Ser)

dbSNP: rs863224440

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197870	SCV000253671	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 2642 of the ATM protein (p.Arg2642Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia and with breast cancer (PMID: 8808599, 26556299; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215980). 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. Studies have shown that this missense change results in skipping of exon 53 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000215938	SCV000278004	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-20	criteria provided, single submitter	clinical testing	The p.R2642S pathogenic mutation (also known as c.7926A>C), located in coding exon 52 of the ATM gene, results from an A to C substitution at nucleotide position 7926. The arginine at codon 2642 is replaced by serine, an amino acid with dissimilar properties. This nucleotide position is well conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This alteration was reported in conjunction with a pathogenic ATM mutation in a patient with ataxia-telangiectasia and was demonstrated to result in transcripts with both exon 55 skipping and exon 54 and 55 skipping (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46, Savitsky K et al. Science, 1995 Jun;268:1749-53). In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000420030	SCV000520897	likely pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing	The R2642S variant has been detected in a cell line derived from a patient with ataxia-telangiectasia, along with two nonsense variants in the ATM gene (Wright et al., 1996). However, it is unknown whether the variant was a somatic change or was present in the germline. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2642S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Several in-silico splice prediction models predict that R2642S may damage the natural splice donor site in intron 53 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence changel is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Division of Medical Genetics, University of Washington	RCV001250432	SCV001424802	uncertain significance	Familial cancer of breast	2019-07-17	criteria provided, single submitter	clinical testing	The c.7926A>C variant has been reported in the literature in a cell line from an individual with ataxia-telangiectasia who also had two truncating ATM variants (Wright 1996). Experimental studies (Wright 1996) and in silico prediction tools suggest that this variant may impact splicing. This variant is not present in population databases (https://gnomad.broadinstitute.org). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Revvity Omics, Revvity	RCV000197870	SCV002022355	pathogenic	Ataxia-telangiectasia syndrome	2019-01-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250432	SCV004209484	likely pathogenic	Familial cancer of breast	2023-09-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001250432	SCV004931846	pathogenic	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7792600, 8808599, 21665257].