Submissions for variant NM_000051.4(ATM):c.8520G>C (p.Leu2840Phe)

gnomAD frequency: 0.00002  dbSNP: rs752652869

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204493	SCV000262318	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2840 of the ATM protein (p.Leu2840Phe). This variant is present in population databases (rs752652869, gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 22649200). ClinVar contains an entry for this variant (Variation ID: 221124). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ATM function (PMID: 26896183). 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.
Ambry Genetics	RCV000219341	SCV000274172	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-20	criteria provided, single submitter	clinical testing	The p.L2840F variant (also known as c.8520G>C), located in coding exon 57 of the ATM gene, results from a G to C substitution at nucleotide position 8520. The leucine at codon 2840 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in the homozygous state in an individual with a clinical diagnosis of ataxia-telangiectasia (Carney EF et al. J. Immunol., 2012 Jul;189:261-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000219341	SCV000682492	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 2840 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). This variant has been reported in the homozygous state in an individual affected with ataxia telangiectasia (PMID: 22649200). Cells derived from this individual have shown decreased ATM protein expression and no detectable ATM protein activity. This variant has been identified in 1/246018 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.
Illumina Laboratory Services, Illumina	RCV000204493	SCV000914481	uncertain significance	Ataxia-telangiectasia syndrome	2018-12-03	criteria provided, single submitter	clinical testing	The ATM c.8520G>C (p.Leu2840Phe) missense variant has been reported in a homozygous state in one study in one individual with classical ataxia telangiectasia (Carney et al. 2012). Functional studies revealed the individual had 5% residual ATM protein expression with no residual enzyme activity. Control data are unavailable for p.Leu2840Phe variant, which is reported at a frequency of 0.000097 in the African population of the Exome Aggregation Consortium but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence, the p.Leu2840Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for ataxia telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV001770156	SCV002004042	uncertain significance	not provided	2024-08-28	criteria provided, single submitter	clinical testing	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: 24123366, 26896183, 22649200, 23532176, 37306523)
Athena Diagnostics	RCV001770156	SCV002770446	uncertain significance	not provided	2022-07-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003237343	SCV003936018	uncertain significance	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	a variant of uncertain significance in the ATM gene (p.Leu2840Phe). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2840 of the ATM protein (p.Leu2840Phe). This variant is present in population databases (rs752652869, gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 22649200). ClinVar contains an entry for this variant (Variation ID: 221124). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging";). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 22649200). 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.
Baylor Genetics	RCV003237343	SCV004210296	uncertain significance	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing