Submissions for variant NM_000051.4(ATM):c.2150G>C (p.Arg717Pro)

gnomAD frequency: 0.00003  dbSNP: rs768874297

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479906	SCV000569088	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2150G>C at the cDNA level, p.Arg717Pro (R717P) at the protein level, and results in the change of an Arginine to a Proline (CGG>CCG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an extrauterine Mullerian carcinoma (Ritterhouse 2016). ATM Arg717Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg717Pro occurs at a position that is not conserved and is not located in a known functional domain (Stracker 2013, Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg717Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000555903	SCV000622310	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 717 of the ATM protein (p.Arg717Pro). This variant is present in population databases (rs768874297, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 420303). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 36029002). 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	RCV000571648	SCV000660505	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-15	criteria provided, single submitter	clinical testing	The p.R717P variant (also known as c.2150G>C), located in coding exon 13 of the ATM gene, results from a G to C substitution at nucleotide position 2150. The arginine at codon 717 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000571648	SCV000911297	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 717 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 4/281976 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779768	SCV000916556	uncertain significance	not specified	2018-03-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2150G>C (p.Arg717Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 0.00001 in 276434 control chromsomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.4e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.2150G>C, has been reported in the literature in an individual diagnosed with a carcinoma (specific location was not indicated in publication from Ritterhouse_2016). This report does not provide an unequivocal conclusion about association of the variant with Ataxia-Telangiectasia. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000571648	SCV002534166	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-16	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002489159	SCV002780976	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-01-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470559	SCV004209434	uncertain significance	Familial cancer of breast	2023-09-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000555903	SCV002077065	uncertain significance	Ataxia-telangiectasia syndrome	2021-04-12	no assertion criteria provided	clinical testing