Submissions for variant NM_000051.4(ATM):c.4148C>T (p.Ser1383Leu)

gnomAD frequency: 0.00004  dbSNP: rs141087784

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212009	SCV000149096	uncertain significance	not provided	2024-05-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or prostate cancer, but also in unaffected controls (PMID: 11505391, 14695186, 15101044, 19781682, 26976419, 28503720, 30306255, 31206626, 33436325, 33471991, 35467778, 35264596); This variant is associated with the following publications: (PMID: 26689913, 26976419, 17333338, 35957908, 14695186, 11505391, 21787400, 15101044, 20346647, 19683821, 26837699, 28503720, 28779002, 30306255, 29641532, 29483558, 19781682, 34426522, 33436325, 30441849, 33471991, 35264596, 30197789, 31206626, 34262154, 35467778, 35534704, 37529773)
Ambry Genetics	RCV000115187	SCV000184168	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-30	criteria provided, single submitter	clinical testing	The p.S1383L variant (also known as c.4148C>T), located in coding exon 27 of the ATM gene, results from a C to T substitution at nucleotide position 4148. The serine at codon 1383 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in individuals diagnosed with breast, ovarian and prostate cancer (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Rummel SK et al. Breast Cancer Res Treat, 2017 Aug;164:593-601; Koczkowska M et al. Cancers (Basel), 2018 Nov;10:; Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000115187	SCV000537543	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1383 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 11505391, 14695186, 15101044, 19781682, 20346647, 21787400, 26976419, 28503720), lung adenocarcinoma (PMID: 26689913), or chronic lymphocytic leukemia (PMID: 26837699). In a large breast cancer case-control study, this variant was reported in 5/60461 cases and 6/53455 controls (OR=0.737, 95%CI 0.225 to 2.414, p-value=0.765; PMID: 33471991). This variant has also been identified in 11/282674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on protein function that has been observed in affected individuals as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459643	SCV000546705	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000459643	SCV000838536	likely benign	Ataxia-telangiectasia syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780883	SCV000918511	uncertain significance	not specified	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4148C>T (p.Ser1383Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 254118 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4148C>T has been reported in the literature in individuals affected with breast cancer (Teraoka_2001, Angele_2003, Guttierez-Enriquez_2004, Tavtigian_2009, Tung_2015, Rummel_2017, Weitzel_2019), ovarian cancer (Koczkowska_2018), HBOC families testing negative for BRCA1/2 (Bonache_2018), prostate cancer (Brady_2022), lung adenocarcinoma in the TGCA cohort (Lu_2015), and CLL (Nadeu_2016), but it was also found in controls (e.g. Dalmasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, and was found in 6/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another (likely) pathogenic variant in an individual undergoing testing due to a personal and family history of breast cancer has been reported at our laboratory (BRCA2 c.9256_9256+1delinsTA), providing supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Gutierrez-Enriquez_2004). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=10) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV000459643	SCV001262667	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	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.
Genetic Services Laboratory, University of Chicago	RCV000780883	SCV002066406	uncertain significance	not specified	2020-11-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4148C>T, in exon 28 that results in an amino acid change, p.Ser1383Leu. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP rs141087784). The p.Ser1383Leu change has been reported in individuals with chronic lymphocytic leukemia, lung cancer, and breast cancer (PMIDs: 11505391, 19781682, 26976419, 14695186, 26837699, 26689913, 15101044). One of the reported breast cancer cases was also identified to have another sequence change in ATM, p.Asp1853Val (PMID: 19781682). The p.Ser1383Leu change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Ser1383Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1383Leu change remains unknown at this time.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251983	SCV002523468	uncertain significance	See cases	2020-01-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PP3
Revvity Omics, Revvity	RCV000459643	SCV003827480	uncertain significance	Ataxia-telangiectasia syndrome	2021-12-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474711	SCV004204278	uncertain significance	Familial cancer of breast	2024-02-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212009	SCV004221035	uncertain significance	not provided	2014-11-11	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022), 30306255 (2018), 28503720 (2017), 26976419 (2016), 19781682 (2009), 14695186 (2003), 11505391 (2001)), lung cancer (PMID: 26689913 (2015)), prostate cancer (PMID: 33436325 (2021), 35467778 (2022)), chronic lymphocytic leukemia (CLL) (PMID: 26837699 (2016)), or ovarian cancer (PMID: 30441849 (2018)). In a large breast cancer association study, the variant was reported in individuals with breast cancer and in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/ATM)). The frequency of this variant in the general population, 0.000047 (6/129022 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780883	SCV005090325	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212009	SCV005199610	uncertain significance	not provided	2023-07-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549550	SCV000805556	uncertain significance	ATM-related disorder	2024-07-09	no assertion criteria provided	clinical testing	The ATM c.4148C>T variant is predicted to result in the amino acid substitution p.Ser1383Leu. This variant has been reported in individuals with a history of breast cancer (Table 1, Teraoka et al. 2001. PubMed ID: 11505391; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A2, Tung et al. 2016. PubMed ID: 26976419; Table 1, Angèle et al. 2003. PubMed ID: 14695186), prostate cancer (reported as uncertain in Table S4, Karlsson et al. 2021. PubMed ID: 33436325), ovarian cancer (Koczkowska M et al. 2018. PubMed ID: 30441849), and chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699), but without data regarding segregation of the variant in affected individuals. Furthermore, in at least one individual, an additional variant was identified in ATM (p.Asp1853Val) (Table A2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127382/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000459643	SCV001458203	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354350	SCV001548946	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ser1383Leu variant was identified in 7 of 7698 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer or chronic lymphocytic leukemia and was not identified in 5276 control chromosomes from healthy individuals (Angele 2003, Gutierrez Enriquez 2004, Nadeu 2015, Tavtigian-2009, Teraoka 2001, Tung 2016). The variant was also identified in dbSNP (ID: rs141087784) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and LOVD 3.0 database (1x). The variant was identified in control databases in 11 of 277016 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004), Other in 2 of 6462 chromosomes (freq: 0.0003), Latino in 1 of 34406 chromosomes (freq: 0.00003), and European in 7 of 126544 chromosomes (freq: 0.00006); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. A study using cell lines from breast cancer cases carrying the variant showed no difference in the constitutive ATM protein level after exposure to ionizing radiation (Angele 2003). The p.Ser1383 residue is conserved across mammals and other organisms, and 5 of 5 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) 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212009	SCV001739687	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212009	SCV001806987	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212009	SCV001906191	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212009	SCV001957949	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212009	SCV001975695	uncertain significance	not provided		no assertion criteria provided	clinical testing