Submissions for variant NM_000051.4(ATM):c.6739A>G (p.Ile2247Val)

gnomAD frequency: 0.00001  dbSNP: rs587781521

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129510	SCV000184284	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	The p.I2247V variant (also known as c.6739A>G), located in coding exon 45 of the ATM gene, results from an A to G substitution at nucleotide position 6739. The isoleucine at codon 2247 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in 2 subjects in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196259	SCV000254134	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2247 of the ATM protein (p.Ile2247Val). This variant is not present in population databases (gnomAD no frequency). 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: 141137). 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. 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.
Counsyl	RCV000196259	SCV000791587	uncertain significance	Ataxia-telangiectasia syndrome	2017-05-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129510	SCV000903687	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2247 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Sema4, Sema4	RCV000129510	SCV002538450	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV002262749	SCV002544608	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	ATM: BP4
Baylor Genetics	RCV003460894	SCV004207096	uncertain significance	Familial cancer of breast	2023-09-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000196259	SCV002076764	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-11	no assertion criteria provided	clinical testing