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

gnomAD frequency: 0.00029  dbSNP: rs201666889

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586538	SCV000149099	uncertain significance	not provided	2023-06-29	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; Decker et al., 2017; 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, 25479140, 20305132, 17623063, 28652578, 29684080, 30166531, 30197789, 30303537, 31882575, 33471991, 33359728, 28779002, 36029002, 30426508)
Ambry Genetics	RCV000115190	SCV000183990	benign	Hereditary cancer-predisposing syndrome	2019-05-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000168302	SCV000218983	benign	Ataxia-telangiectasia syndrome	2024-01-31	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	2023-07-17	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 estimated 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. Nineteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=16) and benign/likely benign (n=3). 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, part of Exact Sciences	RCV004549551	SCV000805559	uncertain significance	ATM-related disorder	2023-03-21	criteria provided, single submitter	clinical testing	The ATM c.4324T>C variant is predicted to result in the amino acid substitution p.Tyr1442His. This variant has been reported in patients with a personal or family history of breast or ovarian cancer as well as patients with chronic lymphocytic leukemia, but has also been reported in control individuals from the same studies (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Broeks et al. 2007. PubMed ID: 17393301; Table S3, Girard et al. 2018. PubMed ID: 30303537; Knappskog et al. 2012. PubMed ID: 22420423; Table S5, Maxwell et al. 2016. PubMed ID: 27153395; Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160416-T-C) and has conflicting interpretations in ClinVar of uncertain, likely benign, and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127385/). While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Athena Diagnostics	RCV000586538	SCV000840939	likely benign	not provided	2023-02-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586538	SCV001148420	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	ATM: PM2, PP3
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 (https://gnomad.broadinstitute.org/). 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	likely benign	not provided	2023-02-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586538	SCV002010816	uncertain significance	not provided	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 ( https://gnomad.broadinstitute.org/variant/11-108160416-T-C ). 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, https://whi.color.com/variant/11-108160416-T-C). 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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000855627	SCV002760566	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000168302	SCV003827478	uncertain significance	Ataxia-telangiectasia syndrome	2022-04-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149793	SCV003837843	uncertain significance	Breast and/or ovarian cancer	2022-06-21	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003482131	SCV004227966	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	curation	PP3, BS1. According to the ACMG standard criteria we chose these criteria: PP3 (supporting pathogenic): REVEL:0.733, BS1 (strong benign): Filtering Allele Frequency >.05%.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586538	SCV004564024	likely benign	not provided	2023-06-20	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.