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

gnomAD frequency: 0.00025  dbSNP: rs150757822

Total submissions: 28

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122863	SCV000166121	benign	Ataxia-telangiectasia syndrome	2025-02-04	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	This alteration is classified as likely 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.
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	2023-09-01	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 domain (IPR014009) 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 0.00035 in 273768 control chromosomes (gnomAD, publications, and FLOSSIES database), predominantly at a frequency of 0.0044 within the Ashkenazi Jewish subpopulation in the gnomAD database. 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. c.5975A>C has been reported in the literature in individuals affected with cancer phenotypes including breast cancer, chronic lymphocytic leukemia, and pancreatic ductal adenocarcinoma, without strong evidence for causality (examples-Castillo-Guardiola_2022, Gervas_2022, Dorling_2021, Bernstein_2010, Skowronska_2011, Navrkalova_2013, Young_2016, Zhang_2015, Tung_2014, Shindo_2017, Tiao_2017, Girard_2019, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17968022, 20305132, 35245693, 33471991, 35763645, 30303537, 35264596, 26689913, 23585524, 28767289, 21933854, 28652578, 31159747, 25186627, 26787654, 26580448). 20 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (benign, n=4; likely benign, n=7; VUS, n=9). 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
GeneKor MSA	RCV000115220	SCV000821864	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492462	SCV000838564	uncertain significance	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000212036	SCV000840947	benign	not specified	2024-10-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115220	SCV000902598	likely benign	Hereditary cancer-predisposing syndrome	2016-05-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588284	SCV002010800	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212036	SCV002065401	likely benign	not specified	2021-06-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115220	SCV002537528	benign	Hereditary cancer-predisposing syndrome	2020-10-21	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000122863	SCV002584739	uncertain significance	Ataxia-telangiectasia syndrome	2022-07-13	criteria provided, single submitter	clinical testing	The ATM c.5975A>C (p.Lys1992Thr) missense change has a maximum subpopulation frequency of 0.43% in gnomAD v2.1.1. The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with a personal and/or family history of breast cancer, prostate cancer, and pancreatic adenocarcinoma (PMID: 28767289, 30303537, 32601921, 33436325). In addition, four individuals with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212036	SCV002760701	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515391	SCV003920237	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-07-12	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in numerous individuals with various types of cancer including breast, prostate and pancreatic ductal adenocarcinoma (Shindo 2017 PMID:28767289, Girard 2019 PMID:30303537, Tsaousis 2019 PMID:31159747, Gerbas 2020 PMID:32601921, Karlsson 2021 PMID:33436325). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.4% (45/10364) including 1 homozygote https://gnomad.broadinstitute.org/variant/11-108183194-A-C?dataset=gnomad_r2_1). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Benign (Variation ID:127415). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588284	SCV004221204	benign	not provided	2018-08-03	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003482132	SCV004227952	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	curation	Homozygous in healthy individual. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls (PM2_sup), BP4 (supporting benign): REVEL: 0.256 BayesDEL:-0.143455, BS2 (strong benign): 1x homozygous in gnomAD (Ashkenazi Jewish), in Tübingen: NGSD counts: 1x hom, 30x het, 0x mosaic (homozygous: healthy mother in exom trio for other disease)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115220	SCV004228096	benign	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492461	SCV004239383	likely benign	Breast and/or ovarian cancer	2023-06-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589569	SCV005084006	likely benign	Familial cancer of breast	2024-05-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CeGaT Center for Human Genetics Tuebingen	RCV000588284	SCV005435910	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP1
True Health Diagnostics	RCV000115220	SCV000805218	likely benign	Hereditary cancer-predisposing syndrome	2018-05-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549560	SCV000805590	likely benign	ATM-related disorder	2022-04-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.