Total submissions: 28
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 |
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, |
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, |
RCV000212036 | SCV000694313 | benign | not specified | 2024-12-23 | 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 0.00036 in 254000 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database, including at least 1 homozygote (2 homozygous individuals in gnomAD v4). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Prostate Cancer phenotype (0.00025) and is also reported at a frequency of 0.0044 within the Ashkenazi Jewish subpopulation in the gnomAD database (which is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia, 0.004), suggesting that the variant might be a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. It has further been reported in at least 4 individuals over the age of 70 years who have never had cancer (FLOSSIES database). 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). 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). ClinVar contains an entry for this variant (Variation ID: 127415). Based on the evidence outlined above, the variant was classified as benign. |
Counsyl | RCV000122863 | SCV000799792 | uncertain significance | Ataxia-telangiectasia syndrome | 2018-05-10 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000115220 | SCV000902598 | likely benign | Hereditary cancer-predisposing syndrome | 2016-05-18 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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, |
RCV000588284 | SCV002010800 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000212036 | SCV002065401 | likely benign | not specified | 2021-06-18 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000115220 | SCV002537528 | benign | Hereditary cancer-predisposing syndrome | 2020-10-21 | criteria provided, single submitter | curation | |
St. |
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, |
RCV000212036 | SCV002760701 | uncertain significance | not specified | 2025-03-04 | criteria provided, single submitter | clinical testing | |
Center for Genomics, |
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, |
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, |
RCV000115220 | SCV004228096 | benign | Hereditary cancer-predisposing syndrome | 2023-09-05 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV003492461 | SCV004239383 | likely benign | Breast and/or ovarian cancer | 2023-06-13 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
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]. |
Ce |
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 | |
Prevention |
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, |
RCV000122863 | SCV001466200 | likely benign | Ataxia-telangiectasia syndrome | 2020-04-03 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
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. |