ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3963G>A (p.Met1321Ile) (rs35184530)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129195 SCV000183934 likely benign Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study
Invitae RCV001079506 SCV000547072 likely benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000657024 SCV000566628 likely benign not provided 2020-11-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28580595, 30287823, 25656989, 28256603, 25742471, 22529920, 26667234, 26787654, 19781682, 17344846, 24728327)
Color Health, Inc RCV000129195 SCV000910722 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120136 SCV001572374 likely benign not specified 2021-04-03 criteria provided, single submitter clinical testing Variant summary: ATM c.3963G>A (p.Met1321Ile) 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 0.00012 in 251186 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 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 East Asian origin. c.3963G>A has been reported in the literature in individuals affected with Breast Cancer and in unaffected controls (example, Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus of benign/likely benign (n=4) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI RCV000120136 SCV000084275 not provided not specified 2013-09-19 no assertion provided reference population
King Laboratory,University of Washington RCV000120136 SCV001251386 benign not specified 2019-09-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355120 SCV001549909 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Met1321Ile variant was identified in 2 of 19,164 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in 9 of 51,952 control chromosomes (frequency: 0.0002) from healthy individuals (Momozawa 2018, Tavtigian 2009). The variant was identified in dbSNP (rs35184530) as “with uncertain significance”, ClinVar (classified as uncertain significance by Invitae and GeneDx and likely benign by Ambry Genetics and Color) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 30 of 282,578 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 28 of 19,938 chromosomes (freq: 0.001), South Asian in 1 of 30612 chromosomes (freq: 0.00003), European in 1 of 128,956 chromosomes (freq: 0.000008), while the variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish and Other populations. The p.Met1321 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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.

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