Submissions for variant NM_000051.4(ATM):c.5645G>A (p.Arg1882Gln)

gnomAD frequency: 0.00001  dbSNP: rs587782236

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130937	SCV000185849	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-22	criteria provided, single submitter	clinical testing	The p.R1882Q variant (also known as c.5645G>A), located in coding exon 36 of the ATM gene, results from a G to A substitution at nucleotide position 5645. The arginine at codon 1882 is replaced by glutamine, an amino acid with highly similar properties. This variant was observed in 1/7051 unselected female breast cancer patients and was not observed in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also detected in a cohort of 337 high risk hereditary breast and/or ovarian cancer patients who previously tested negative for pathogenic BRCA1/2 variants (Schubert S et al. Int J Cancer, 2019 06;144:2683-2694). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530461	SCV000622610	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1882 of the ATM protein (p.Arg1882Gln). This variant is present in population databases (rs587782236, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 30287823). ClinVar contains an entry for this variant (Variation ID: 142104). 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 glutamine 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260302	SCV001437224	uncertain significance	not specified	2020-09-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5645G>A (p.Arg1882Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5645G>A has been reported in the literature in individuals affected with Breast Cancer (Tung_2015, Momozawa_2018, Schubert_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130937	SCV001733570	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1882 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 been reported in individuals affected with breast and/or ovarian cancer (PMID: 25186627, 30287823, 30426508). This variant has been identified in 1/250786 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	RCV000130937	SCV002529057	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001260302	SCV002760591	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003314563	SCV004014251	uncertain significance	not provided	2023-06-30	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 individuals with breast cancer and in unaffected control(s) (Tung et al., 2015; Momozawa et al., 2018; Schubert et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 30426508, 25186627, 30287823)
Baylor Genetics	RCV003467161	SCV004209529	uncertain significance	Familial cancer of breast	2023-08-31	criteria provided, single submitter	clinical testing