Submissions for variant NM_000051.4(ATM):c.320G>A (p.Cys107Tyr)

gnomAD frequency: 0.00062  dbSNP: rs142358238

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589242	SCV000149082	uncertain significance	not provided	2017-12-15	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.320G>A at the cDNA level, p.Cys107Tyr (C107Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in the compound heterozygous state with a nonsense variant in one individual with Ataxia-telangiectasia (A-T), whose diagnosis was confirmed by clinical observation and radiation sensitivity testing (Bernstein 2003). This variant was also observed in at least two individuals undergoing hereditary cancer testing (Yorczyk 2014, Yurgelun 2015), and in at least one individual with acute myeloid leukemia (Lu 2015). Hirsch et al. (2008) did not identify ATM Cys107Tyr in a series of 31 African-American individuals with breast cancer, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 2/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Cys107Tyr was observed at an allele frequency of 0.21% in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Cys107Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115173	SCV000186495	likely benign	Hereditary cancer-predisposing syndrome	2019-02-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000198992	SCV000254081	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115173	SCV000576456	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515352	SCV000611357	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260261	SCV000694251	likely benign	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.320G>A (p.Cys107Tyr) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of 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 0.00017 in 250912 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.320G>A has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Bernstein_2003), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), an unaffected control of African American ancestry (Hirsch_2008), a patient undergoing multigene panel testing for cancer (Yorczyk_2015), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), a patient with AML in the TGCA cohort (Lu_2015), a cerebellar ataxia patient (Coutelier_2018), breast cancer cases and controls (Weitzel_2019, Eygelaar_2022, Guindalini_2022) and in PDAC patients (Zimmermann_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. Additionally, the variant was found to occur in eleven women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and seven ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over six years of evaluations performed at our laboratory spanning the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000198992	SCV000792422	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000198992	SCV000838468	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000589242	SCV000861414	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115173	SCV000910674	likely benign	Hereditary cancer-predisposing syndrome	2015-10-29	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225317	SCV002504989	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115173	SCV002535813	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003407491	SCV004115894	uncertain significance	ATM-related condition	2024-01-01	criteria provided, single submitter	clinical testing	The ATM c.320G>A variant is predicted to result in the amino acid substitution p.Cys107Tyr. This variant has been reported with a nonsense variant in the compound heterozygous state in an individual with ataxia telangiectasia (Bernstein et al. 2003. PubMed ID: 12673797). It has also been observed in an individual with acute myeloid leukemia (Lu et al. 2015. PubMed ID: 26689913, supplementary data 12), and in another individual with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, supplemental table 2). However, it has also been observed in four individuals with breast cancer (Eygelaar et al. 2022. PubMed ID: 35039564; Table S3, Guindalini et al. 2022. PubMed ID: 35264596) and found in a control individual from a breast cancer study (Hirsch et al. 2008. PubMed ID: 17333338). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127368/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589242	SCV004220955	likely benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357199	SCV001552587	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Cys107Tyr variant was identified in 4 of 36,874 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia tenlangiectasia, acute myeloid leukemia, Lynch Syndrome or breast cancer and was present in 3 of 11,166 control chromosomes (frequency: 0.0003) from healthy individuals (Bernstein 2003, Lu 2015, Yurgelun 2015, Hirsch 2008, Decker 2017). The variant was identified in dbSNP (rs142358238) as “with other allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx, Counsyl and 5 other submitters; and as likely benign by Ambry Genetics and Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 60 of 281,758 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 53 of 24,862 chromosomes (freq: 0.002), Latino in 6 of 35,344 chromosomes (freq: 0.0002), and South Asian in 1 of 30,544 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European or Other populations. This variant was identified in the compound heterozygous state in an individual with ataxia telangiectasia with a co-occurring, pathogenic ATM variant (c.7327C>T, p.Arg2443*; Bernstein 2003). The p.Cys107 residue is conserved in mammals but not in more distantly related organisms, although four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Genetic Services Laboratory, University of Chicago	RCV001260261	SCV003840070	likely benign	not specified	2022-09-09	no assertion criteria provided	clinical testing