Submissions for variant NM_000051.4(ATM):c.334G>A (p.Ala112Thr)

gnomAD frequency: 0.00080  dbSNP: rs146382972

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588561	SCV000149084	likely benign	not provided	2020-09-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25318351, 25980754, 17333338, 27443514, 27720647, 19781682, 28779002, 23555315, 33095795)
Ambry Genetics	RCV000115175	SCV000186494	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: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195412	SCV000254082	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115175	SCV000576457	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211948	SCV000593494	uncertain significance	not specified	2016-10-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515264	SCV000611359	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	RCV000211948	SCV000694259	benign	not specified	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.334G>A (p.Ala112Thr) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 250408 control chromosomes (gnomAD, Hirsch_2008), predominantly at a frequency of 0.0028 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 3 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. The variant has also been found in 13/2559 (carrier freq=0.00508) African American women over the age of 70 without history of cancer (FLOSSIES dataset). c.334G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome, endometrial carcinoma, cerebellar ataxia, primary ovarian insufficiency and PDAC (examples: Tung_2014, Yurgelun_2015, Ring_2016, Coutelier_2018, Mullins_2019, Weitzel_2019, Franca_2020, Zimmermann_2021), but it was also reported in healthy controls (examples: Hirsch_2008, Weitzel_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. Ten ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, three as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000195412	SCV000838469	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000588561	SCV000861417	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115175	SCV000902684	benign	Hereditary cancer-predisposing syndrome	2015-11-10	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225318	SCV002504992	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588561	SCV004220968	likely benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589562	SCV005083904	likely benign	Familial cancer of breast	2024-04-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354149	SCV001548692	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ala112Thr variant was identified in 4 of 17948 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or Lynch syndrome and was present in 2 of 4988 control chromosomes (frequency: 0.0004) from healthy individuals (Haiman 2013, Hirsch 2008, Ring 2016, Tavtigian 2009, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs146382972) as "With other allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and five other submitters), and MutDB. The variant was not identified in COGR, Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 74 of 276196 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 66 of 23976 chromosomes (freq: 0.003), Other in 1 of 6434 chromosomes (freq: 0.0002), and Latino in 7 of 34316 chromosomes (freq: 0.0002), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala112 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
PreventionGenetics, part of Exact Sciences	RCV004549547	SCV004107223	uncertain significance	ATM-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The ATM c.334G>A variant is predicted to result in the amino acid substitution p.Ala112Thr. This variant has been reported in two individuals with breast cancer (Tung et al. 2014. PubMed ID: 25186627; Mullins and Gupta. 2019. PubMed ID: 31719806), in an individual with endometrial cancer (Ring et al. 2016. PubMed ID: 27443514, Table S2), an individual with primary ovarian insufficiency (França et al. 2020. PubMed ID: 33095795), and in at least two individuals undergoing Lynch syndrome genetic testing (Yorczyk et al. 2014. PubMed ID: 25318351, Table 2; Yurgelun et al. 2015. PubMed ID: 25980754, Table S2). It has also been reported in controls from breast cancer cohort studies (Hirsch et al. 2007. PubMed ID: 17333338; Tavtigian et al. 2009. PubMed ID: 19781682. Table S2). This variant is reported in 0.27% of alleles in individuals of African descent in gnomAD, which is significantly more common than other known disease-causing ATM variants. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127370/). 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.