Submissions for variant NM_000051.4(ATM):c.538C>A (p.Gln180Lys)

dbSNP: rs730881333

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479337	SCV000566409	uncertain significance	not provided	2019-05-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555249	SCV000622583	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 180 of the ATM protein (p.Gln180Lys). This variant is present in population databases (rs730881333, gnomAD 0.0009%). 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: 418960). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000772112	SCV000905166	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 180 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 been identified in 1/246194 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.
Ambry Genetics	RCV000772112	SCV001185968	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-06	criteria provided, single submitter	clinical testing	The p.Q180K variant (also known as c.538C>A), located in coding exon 5 of the ATM gene, results from a C to A substitution at nucleotide position 538. The glutamine at codon 180 is replaced by lysine, an amino acid with similar properties. This amino acid position is well 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.
Sema4, Sema4	RCV000772112	SCV002528442	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	curation
Baylor Genetics	RCV003463986	SCV004207760	uncertain significance	Familial cancer of breast	2023-08-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000555249	SCV002094041	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-28	no assertion criteria provided	clinical testing