Submissions for variant NM_000051.4(ATM):c.6178C>T (p.Arg2060Cys)

dbSNP: rs587778078

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766513	SCV000149136	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in breast cancer case-control studies in both cases and unaffected controls (Decker et al., 2017; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 24728327, 27882345, 33471991, 23532176, 28779002)
Ambry Genetics	RCV000115227	SCV000214922	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-02	criteria provided, single submitter	clinical testing	The p.R2060C variant (also known as c.6178C>T), located in coding exon 41 of the ATM gene, results from a C to T substitution at nucleotide position 6178. The arginine at codon 2060 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204186	SCV000259404	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2060 of the ATM protein (p.Arg2060Cys). This variant is present in population databases (rs587778078, gnomAD 0.006%). 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: 127422). 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.
Color Diagnostics, LLC DBA Color Health	RCV000115227	SCV000687676	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2060 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 5/251296 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.
Sema4, Sema4	RCV000115227	SCV002537166	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	curation
Baylor Genetics	RCV004566995	SCV005057113	uncertain significance	Familial cancer of breast	2023-12-28	criteria provided, single submitter	clinical testing
ITMI	RCV000120152	SCV000084293	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000204186	SCV002078108	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739395	SCV005361232	uncertain significance	ATM-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The ATM c.6178C>T variant is predicted to result in the amino acid substitution p.Arg2060Cys. This variant has been reported in an individual from a healthy, ancestrally diverse genome sequencing cohort (Table 1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127422/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.