Submissions for variant NM_000051.4(ATM):c.9128A>G (p.Lys3043Arg)

gnomAD frequency: 0.00001  dbSNP: rs867893961

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000237056	SCV000293945	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534818	SCV000622888	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 3043 of the ATM protein (p.Lys3043Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biliary tract cancer (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 246403). 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.
Ambry Genetics	RCV000573858	SCV000660760	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-29	criteria provided, single submitter	clinical testing	The p.K3043R variant (also known as c.9128A>G), located in coding exon 62 of the ATM gene, results from an A to G substitution at nucleotide position 9128. The lysine at codon 3043 is replaced by arginine, an amino acid with highly similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573858	SCV000905064	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 3043 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798745	SCV002042339	uncertain significance	Breast and/or ovarian cancer	2019-07-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000534818	SCV002083287	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-29	no assertion criteria provided	clinical testing