ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5975A>C (p.Lys1992Thr) (rs150757822)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588284 SCV000149129 likely benign not provided 2021-03-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26580448, 17968022, 28652578, 21933854, 26689913, 23585524, 26787654, 24113346, 29769598, 29522266, 31159747, 30303537, 32601921, 33436325, 28767289)
Invitae RCV000122863 SCV000166121 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115220 SCV000172870 likely benign Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Subpopulation frequency in support of benign classification
Fulgent Genetics,Fulgent Genetics RCV000515391 SCV000611369 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 RCV000212036 SCV000694313 likely benign not specified 2018-10-01 criteria provided, single submitter clinical testing Variant summary: ATM c.5975A>C (p.Lys1992Thr) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 0.00034 in 297344 control chromosomes (gnomAD, FLOSSIES and publication data), predominantly observed within the Ashkenazi Jewish subpopulation at a frequency of 0.0044 in the gnomAD database, including 1 homozygote. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), suggesting that the variant might be a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. The variant, c.5975A>C, has been reported in the literature in individuals with breast cancer, chronic lymphocytic leukemia, and pancreatic ductal adenocarcinoma, however, without clear evidence supporting pathogenicity (Bernstein_2010, Skowronska_2011, Navrkalova_2013, Young_2016, Zhang_2015, Tung_2014, Shindo_2017, Tiao_2017). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign x4, VUS x3). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000122863 SCV000799792 uncertain significance Ataxia-telangiectasia syndrome 2018-05-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588284 SCV000805590 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115220 SCV000821864 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000122863 SCV000838564 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000588284 SCV000840947 benign not provided 2018-08-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115220 SCV000902598 likely benign Hereditary cancer-predisposing syndrome 2016-05-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122863 SCV001263990 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Pars Genome Lab RCV000122863 SCV001736839 likely benign Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115220 SCV000805218 likely benign Hereditary cancer-predisposing syndrome 2018-05-03 no assertion criteria provided clinical testing
Natera, Inc. RCV000122863 SCV001466200 likely benign Ataxia-telangiectasia syndrome 2020-04-03 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358376 SCV001554091 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Lys1992Thr variant was identified in 1 of 636 proband chromosomes (frequency: 0.002) from British individuals or families with chronic lymphocytic leukemia and was present in 1 of 562 control chromosomes (frequency: 0.002) from healthy individuals (Skowronska 2012). The variant was also identified in dbSNP (ID: rs150757822) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Invitae and Ambry Genetics) and Clinvitae (2X). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 92 (1 homozygous) of 277014 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Lys1992 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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