ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.334G>A (p.Ala112Thr) (rs146382972)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588561 SCV000149084 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.334G>A at the cDNA level, p.Ala112Thr (A112T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Hirsch et al. (2008) did not identify this variant in a series of 31 breast cancer cases of African American ancestry, 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 0/5,488 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). This variant has also been reported in at least two individuals undergoing multi-gene cancer panel testing based on a history of endometrial cancer or a Lynch-syndrome associated cancer and/or polyps (Yurgelun 2015, Ring 2016). ATM Ala112Thr was observed at an allele frequency of 0.27% (66/23,976) 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ala112Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115175 SCV000186494 likely benign Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting benign classification
Invitae RCV000195412 SCV000254082 benign Ataxia-telangiectasia syndrome 2020-12-08 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 likely benign not specified 2020-10-29 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 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 0.00025 in 270176 control chromosomes, 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 2.8 fold- 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.334G>A has been reported in the literature in individuals affected with Breast Cancer, Lynch Syndrome, and endometrial carcinoma, but also healthy controls (examples: Hirsch_2008, Haiman_2013, Tung_2014, Yorczyk_2015, Yurgelun_2015, Ring_2016, Mullins_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. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=6) and benign/ likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000195412 SCV000838469 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000588561 SCV000861417 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115175 SCV000902684 benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
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.

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