ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1444A>C (p.Lys482Gln) (rs202173660)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211962 SCV000149051 uncertain significance not provided 2019-11-07 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast and colon cancers (Tung 2015, Decker 2017, Yurgelun 2017, Hauke 2018); This variant is associated with the following publications: (PMID: 28779002, 25231023, 25528188, 28528518, 28135145, 25186627, 28873162, 29522266, 28652578, 31159747)
Ambry Genetics RCV000115142 SCV000172911 likely benign Hereditary cancer-predisposing syndrome 2020-09-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study
Invitae RCV000197378 SCV000254060 likely benign Ataxia-telangiectasia syndrome 2020-12-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115142 SCV000537540 likely benign Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing
Counsyl RCV000197378 SCV000800380 uncertain significance Ataxia-telangiectasia syndrome 2018-06-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115142 SCV000821831 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000197378 SCV000838488 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000211962 SCV000840917 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779759 SCV000916535 uncertain significance not specified 2020-11-04 criteria provided, single submitter clinical testing Variant summary: ATM c.1444A>C (p.Lys482Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251370 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (9.5e-05 vs 0.001), allowing no conclusion about variant significance. c.1444A>C has been reported in the literature in individuals affected with various types of cancer (HBOC, colorectal cancer, Mullerian adenosarcoma) without strong evidence for causality (Cock-Rada_2017, Yurgelun_2017, Howitt_2019, Tsaousis_2019, Urbina-Jara_2019, Mandelker_2017). 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 without evidence for independent evaluation, seven classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000197378 SCV001482692 uncertain significance Ataxia-telangiectasia syndrome 2020-11-18 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000211962 SCV001549155 uncertain significance not provided no assertion criteria provided clinical testing The ATM p.Lys482Gln variant was identified in 1 of 170 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Cock-Rada_2017). The p.Lys482Gln variant was also found in one study to be a recurrent variant in Mullerian adenosarcoma occurring in 3 of 36 chromosomes (frequency: 0.083) Howitt_2015). The variant was also identified in the following databases: dbSNP (ID: rs202173660) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Color Genomics), Clinvitae (3x), and Cosmic (1x in endometrial cancer). The variant was not identified in MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 25 of 246152 chromosomes at a frequency of 0.000102 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15302 chromosomes (freq: 0.000065), Other in 1 of 5482 chromosomes (freq: 0.000182), Latino in 1 of 33566 chromosomes (freq: 0.00003), European (Non-Finnish) in 22 of 111630 chromosomes (freq: 0.000197); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Lys482 residue is not 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, HumanSpliceFinder) 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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