Submissions for variant NM_000051.4(ATM):c.5189G>A (p.Arg1730Gln)

gnomAD frequency: 0.00003  dbSNP: rs373789346

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212028	SCV000149116	uncertain significance	not provided	2024-10-31	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, or other cancers, but also in unaffected controls (PMID: 28652578, 30093976, 30287823, 32980694, 36243179); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28652578, 28481359, 22071889, 29642553, 30287823, 30093976, 31422574, 33176972, 32980694, 36746516, 36243179, 35534704)
Ambry Genetics	RCV000115207	SCV000217480	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The p.R1730Q variant (also known as c.5189G>A), located in coding exon 34 of the ATM gene, results from a G to A substitution at nucleotide position 5189. The arginine at codon 1730 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/110 Asian patients with multiple malignancies who underwent testing for hereditary cancer predisposition in a patient with a personal history of ovarian and endometrial cancers (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This alteration has also been reported with a carrier frequency of 4 in 7,051 unselected breast cancer patients and 1 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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	RCV000197381	SCV000254120	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-15	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 1730 of the ATM protein (p.Arg1730Gln). This variant is present in population databases (rs373789346, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and chronic lymphocytic leukemia (PMID: 28652578, 30287823). ClinVar contains an entry for this variant (Variation ID: 127402). 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 disruptive. 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	RCV000115207	SCV000687609	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1730 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several case-control studies. In a large international cohort, this variant was reported in 4/60466 breast cancer cases and 3/53461 controls (OR=1.179, 95%CI 0.264 to 5.268; PMID: 33471991). In a study conducted in Japan, this variant was identified in 4/7051 women affected with breast cancer and 1/11241 controls (OR=6.378, 95%CI 0.6 to 313.6; PMID: 30287823). In a case-control study of chronic lymphocytic leukemia, this variant was found in 1/644 cases and 4/8916 controls (PMID: 28652578). This variant has also been reported in an individual affected with ovarian and endometrial cancer (PMID: 30093976). This variant was identified in 5/282500 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	RCV000780913	SCV000918559	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5189G>A (p.Arg1730Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251120 control chromosomes (gnomAD). In addition, the variant was also reported in 13 heterozygotes from about 38,000 healthy Japanese individuals (in the jMorp database, PMID: 33179747). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5189G>A has been reported in the literature in individuals affected with different types of cancers, including breast and/or ovarian cancer (Tiao_2017, Jiang_2018, Chan_2018, Momozawa_2018, Neeb_2021), however it was also found in controls (Momozawa_2018) and in non-cancer related cohorts (e.g. Kraemer_2019). Furthermore, the variant was reported in 1/7325 European American women, who are older than age 70 years, and who have never had cancer (in the FLOSSIES database). 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. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000197381	SCV001138514	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000197381	SCV001737311	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-10	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243761	SCV002512241	uncertain significance	Familial cancer of breast	2021-07-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate
Sema4, Sema4	RCV000115207	SCV002528331	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
Athena Diagnostics	RCV000212028	SCV002771615	uncertain significance	not provided	2021-10-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505031	SCV002816398	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-10-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002243761	SCV004210247	uncertain significance	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000197381	SCV001550795	uncertain significance	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing	The ATM p.Arg1730Gln variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, and LOVD 3.0 (not available). The variant was identified in dbSNP (ID: rs373789346) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics and Invitae), Clinvitae (3x), and in control databases in 5 of 276816 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following population: European Non-Finnish in 5 of 126368 chromosomes (frequency: 0.00004). The p.Arg1730 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the Gln variant impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000197381	SCV002080917	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-10	no assertion criteria provided	clinical testing