Submissions for variant NM_000051.4(ATM):c.6179G>C (p.Arg2060Pro)

gnomAD frequency: 0.00004  dbSNP: rs376521407

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221500	SCV000274556	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-18	criteria provided, single submitter	clinical testing	The p.R2060P variant (also known as c.6179G>C), located in coding exon 41 of the ATM gene, results from a G to C substitution at nucleotide position 6179. The arginine at codon 2060 is replaced by proline, an amino acid with 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	RCV000459766	SCV000547100	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-25	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 2060 of the ATM protein (p.Arg2060Pro). This variant is present in population databases (rs376521407, gnomAD 0.02%). 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: 230875). 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.
GeneDx	RCV000482223	SCV000564649	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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)
Color Diagnostics, LLC DBA Color Health	RCV000221500	SCV000906525	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline 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 ATM-related disorders in the literature. This variant has been identified in 3/282654 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	RCV000779773	SCV000916563	uncertain significance	not specified	2018-01-08	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.6179G>C (p.Arg2060Pro) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/276988 control chromosomes (gnomAD) at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Other missense changes this residue (Arg2060Leu, Arg2060His and Arg2060Cys) have been classified as uncertain significance by clinical laboratories in ClinVar. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Athena Diagnostics	RCV000482223	SCV001475563	uncertain significance	not provided	2020-02-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462450	SCV004207724	uncertain significance	Familial cancer of breast	2023-08-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000459766	SCV002080968	uncertain significance	Ataxia-telangiectasia syndrome	2020-12-30	no assertion criteria provided	clinical testing