Submissions for variant NM_000051.4(ATM):c.2150G>A (p.Arg717Gln)

dbSNP: rs768874297

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485077	SCV000568987	uncertain significance	not provided	2023-11-07	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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Observed in individuals with a personal and/or family history of breast or prostate cancer (PMID: 31871109, 26911350, 31214711); This variant is associated with the following publications: (PMID: 31871109, 26911350, 31214711)
Ambry Genetics	RCV000573560	SCV000668042	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.R717Q variant (also known as c.2150G>A), located in coding exon 13 of the ATM gene, results from a G to A substitution at nucleotide position 2150. The arginine at codon 717 is replaced by glutamine, an amino acid with highly similar properties. One study detected this alteration in 1/141 unrelated Indian patients and families with breast and/or ovarian cancer (Mannan AU et al. J. Hum. Genet., 2016 Jun;61:515-22). In a study of 196 women with breast cancer and 185 unaffected controls from Cameroon and Uganda, this variant was observed in a woman from Uganda (Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). This alteration has also been reported with a carrier frequency of 0.00013 in 7,636 unselected prostate cancer patients and was not detected in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). 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	RCV000628158	SCV000749051	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-27	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 717 of the ATM protein (p.Arg717Gln). This variant is present in population databases (rs768874297, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 26911350). ClinVar contains an entry for this variant (Variation ID: 420250). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000573560	SCV000913556	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 717 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 an individual affected with breast cancer (PMID: 26911350). This variant has been identified in 5/250664 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.
Genetic Services Laboratory, University of Chicago	RCV001821396	SCV002068949	uncertain significance	not specified	2018-04-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002489158	SCV002779389	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-24	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315430	SCV004015183	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 732 of the ATM protein (p.Met732Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Baylor Genetics	RCV003315430	SCV004207126	uncertain significance	Familial cancer of breast	2023-09-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000628158	SCV002077054	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-17	no assertion criteria provided	clinical testing