rs150757822
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_000051.4(ATM):c.5975A>C(p.Lys1992Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,590,620 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1992R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5975A>C | p.Lys1992Thr | missense_variant | 40/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5975A>C | p.Lys1992Thr | missense_variant | 40/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000250 AC: 38AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000362 AC: 91AN: 251040Hom.: 1 AF XY: 0.000361 AC XY: 49AN XY: 135782
GnomAD4 exome AF: 0.000213 AC: 306AN: 1438256Hom.: 2 Cov.: 29 AF XY: 0.000211 AC XY: 151AN XY: 716890
GnomAD4 genome ? AF: 0.000249 AC: 38AN: 152364Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74508
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 03, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 13, 2022 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2018 | 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 05, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 18, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | May 03, 2018 | - - |
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2021 | This variant is associated with the following publications: (PMID: 26580448, 17968022, 28652578, 21933854, 26689913, 23585524, 26787654, 24113346, 29769598, 29522266, 31159747, 30303537, 32601921, 33436325, 28767289) - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 03, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2018 | - - |
not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 18, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2023 | 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. - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jul 12, 2022 | 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. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Hereditary cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 13, 2023 | - - |
ATM-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 01, 2022 | 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). - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 28, 2024 | 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]. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Jan 05, 2024 | 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) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at