Submissions for variant NM_000051.4(ATM):c.2159G>A (p.Arg720His)

gnomAD frequency: 0.00002  dbSNP: rs55830714

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211974	SCV000209695	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast and prostate cancer but also seen in controls (PMID: 28779002, 30287823, 31214711, 34262154, 33471991); This variant is associated with the following publications: (PMID: 35218119, 36243179, 19781682, 25428177, 27284491, 28415633, 22529920, 28779002, 25925381, 30287823, 33471991, 29338689, 34262154, 33588785, 32566746, 31214711, 20305132, 32068069, 28743247)
Ambry Genetics	RCV000159689	SCV000217564	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-21	criteria provided, single submitter	clinical testing	The p.R720H variant (also known as c.2159G>A), located in coding exon 13 of the ATM gene, results from a G to A substitution at nucleotide position 2159. The arginine at codon 720 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in 1/4,112 breast cancer patients and 0/2,399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was observed in with an allele frequency of 0.00142 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00249 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0015 in 12,490 male controls of Japanese ancestry(Momozawa Y et al, 2018 10;9:4083). This alteration has also been reported with a carrier frequency of 0.00196 in 7,636 unselected prostate cancer patients and 0.0015 in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This alteration has also been reported in at least one subject in a study of 13,087 breast cancer cases and 5,488 control individuals in the UK (Decker B et al, 2017 11;54:732-741). This amino acid position is poorly 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	RCV000205354	SCV000261508	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 720 of the ATM protein (p.Arg720His). This variant is present in population databases (rs55830714, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer, melanoma, ovarian cancer, and/or urothelial cancer (PMID: 20305132, 28779002, 30287823, 32068069, 33588785, 34262154). ClinVar contains an entry for this variant (Variation ID: 181924). 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	RCV000159689	SCV000682032	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 720 of the ATM protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132) including three case-control studies (PMID: 28743247, 30287823, 33471991). In the first case-control study, conducted in the UK, this variant was reported in 1/13087 breast cancer cases and 0/5488 controls (PMID: 28743247). In a second case-control study with Japanese participants, this variant was reported in 10/7051 female breast cancer cases, 28/11241 female controls (OR=0.569, 95%CI 0.2 to 1.2), 0/53 male breast cancer cases, and 19/12490 male controls (PMID: 30287823). A third case-control study included participants from multiple countries and reported this variant in 9/60457 breast cancer cases and 8/53453 controls (OR=0.995, 95%CI 0.384 to 2.578, p-value=1; PMID: 33471991). This variant has been identified in 15/282402 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.
Mendelics	RCV000205354	SCV001138469	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030522	SCV001193470	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174912	SCV001338345	uncertain significance	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2159G>A (p.Arg720His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 298502 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0002 vs 0.001), allowing no conclusion about variant significance. c.2159G>A has been reported in the literature in individuals affected with Breast Cancer/or Ovarian cancer (examples: Bernstein_2010, Momozawa_2018, Kwong_2020, Dalmasso_2021 and Dorling_2021) but also in unaffected controls (examples: Momozawa_2018,and Dorling_2021). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798544	SCV002041950	uncertain significance	Breast and/or ovarian cancer	2019-11-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001174912	SCV004027170	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551371	SCV004119918	uncertain significance	ATM-related disorder	2023-02-21	criteria provided, single submitter	clinical testing	The ATM c.2159G>A variant is predicted to result in the amino acid substitution p.Arg720His. This variant has been reported in individuals with breast and/or ovarian cancer (Table S2, Berstein et al. 2010. PubMed: 20305132; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S1, Kwong et al. 2020. PubMed ID: 32068069). It has been reported in a urothelial carcinoma specimen (Additional Data 3, Yang et al. 2021. PubMed ID: 33588785) and a melanoma cohort study (Supplement, Dalmasso et al. 2021. PubMed ID: 34262154). It has also been reported in cases and controls from a breast cancer cohort study and a prostate cancer cohort study (Supplement, Momozawa et al. 2018. PubMed ID: 30287823; Supplement, Momozawa et al. 2020. PubMed ID: 31214711). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108126976-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/181924/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000211974	SCV001906023	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000211974	SCV001954202	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000205354	SCV002077087	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-24	no assertion criteria provided	clinical testing