ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4324T>C (p.Tyr1442His)

gnomAD frequency: 0.00013  dbSNP: rs201666889
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586538 SCV000149099 uncertain significance not provided 2022-06-07 criteria provided, single submitter clinical testing Observed in individuals with leukemia, breast, ovarian, and/or colorectal cancer, but also in unaffected controls (Broeks et al., 2008; Tavtigian et al., 2009; Knappskog et al., 2012; Lu et al., 2015; Maxwell et al., 2016; Tung et al., 2016; Tiaoet al., 2017; Yehia et al., 2018; Jarhelle et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22420423, 26976419, 20346647, 17393301, 19781682, 26420498, 24172824, 21787400, 23555315, 26689913, 27153395, 27067391, 28652578, 25479140, 20305132, 17623063, 29684080, 30166531, 30197789, 30303537, 31882575)
Ambry Genetics RCV000115190 SCV000183990 benign Hereditary cancer-predisposing syndrome 2019-05-14 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000168302 SCV000218983 benign Ataxia-telangiectasia syndrome 2021-12-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515173 SCV000611361 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115190 SCV000682195 likely benign Hereditary cancer-predisposing syndrome 2020-07-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855627 SCV000694275 likely benign not specified 2022-02-22 criteria provided, single submitter clinical testing Variant summary: ATM c.4324T>C (p.Tyr1442His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 255904 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00032 vs 0.001), allowing no conclusion about variant significance. c.4324T>C has been reported in the literature in individuals affected with Breast Cancer. However, a recent case-control study showed that this variant had higher allele frequency in controls than in cases (Dorling_2021), suggesting this variant is benign. Thirteen 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 (benign/likely benign n=3, VUS n=10). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000168302 SCV000745125 uncertain significance Ataxia-telangiectasia syndrome 2017-06-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586538 SCV000805559 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000586538 SCV000840939 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586538 SCV001148420 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001257491 SCV001434302 uncertain significance Familial cancer of breast 2020-04-09 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with breast and/or ovarian cancer (Broecks 2008, Tavtigian 2009, Knappskog 2012, Lu 2015, Maxell 2016, Tung 2016). This variant has an overall allele frequency of 0.0003 in the Broad Institute gnomAD Browser ( In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586538 SCV001469351 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001257491 SCV002010816 uncertain significance Familial cancer of breast 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000855627 SCV002068619 uncertain significance not specified 2020-02-17 criteria provided, single submitter clinical testing DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4324T>C, in exon 29 that results in an amino acid change, p.Tyr1442His. The p.Tyr1442His change has been reported in individuals with breast cancer (PMID: 19781682, 27153395, 17393301, 22420423, 26976419, 26689913), as well as in a case-control study for chronic lymphocytic leukemia (PMID: 28652578). This sequence change has been described in the gnomAD database with a frequency of 0.061% in European populations (dbSNP rs201666889). The p.Tyr1442His change affects a highly conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. The p.Tyr1442His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Tyr1442His change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000168302 SCV002525966 uncertain significance Ataxia-telangiectasia syndrome 2022-01-22 criteria provided, single submitter clinical testing The ATM c.4324T>C (p.Tyr1442His) missense change has a maximum frequency of 0.060% in gnomAD v2.1.1 ( ). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with breast cancer (PMID: 17393301, 17623063, 19781682, 20346647, 22420423, 25186627, 26976419, 28779002, 29522266, 30303537, 31882575, 32885271, 34445631), Ewing sarcoma (PMID: 33332384), high grade glioma (PMID: 26580448), pancreatic cancer (PMID: 25479140), colorectal cancer (PMID: 29338072, 30166531), and chronic lymphocytic leukemia (PMID: 24172824, 28652578). Other studies have observed this variant in relatively equal numbers of cases and controls (PMID: 19781682, 28652578, 30303537). In addition, four individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Sema4,Sema4 RCV000115190 SCV002534656 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-26 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV001257491 SCV002579095 uncertain significance Familial cancer of breast 2022-07-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355810 SCV001550802 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Tyr1442His variant was identified in 7 of 11034 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, and was not identified in 4798 control chromosomes from healthy individuals (Broeks 2008, Knappskog 2012, Maxwell 2016, Tavtigian 2009, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs201666889) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Invitae, Color Genomics and two clinical laboratories; classified as benign by Ambry Genetics), and LOVD 3.0 (VUS). The variant was not identified in the GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 82 of 276704 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 6442 chromosomes (freq: 0.000155), European Non-Finnish in 76 of 126378 chromosomes (freq: 0.001), European Finnish in 5 of 25776 chromosomes (freq: 0.0002); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Tyr1442 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. This variant was observed in one individual from our lab with a co-occurring pathogenic variant in CHEK2, c.1100delC, increasing the likelihood this variant does not have clinical significance. 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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