rs779718362
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000051.4(ATM):āc.4631A>Gā(p.Tyr1544Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,561,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 31)
Exomes š: 0.000034 ( 0 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 3.11
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.78
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4631A>G | p.Tyr1544Cys | missense_variant | 31/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4631A>G | p.Tyr1544Cys | missense_variant | 31/63 | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000332 AC: 8AN: 240752Hom.: 0 AF XY: 0.0000307 AC XY: 4AN XY: 130218
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GnomAD4 exome AF: 0.0000341 AC: 48AN: 1409584Hom.: 0 Cov.: 28 AF XY: 0.0000356 AC XY: 25AN XY: 702792
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74334
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:13Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 24, 2019 | The ATM c.4631A>G; p.Tyr1544Cys variant (rs779718362) is reported in the literature in individuals with breast cancer (Edvardsen 2007, Tung 2015), and is also reported in ClinVar (Variation ID: 245791). This variant is found in the general population with an overall allele frequency of 0.003% (8/240752 alleles) in the Genome Aggregation Database. The tyrosine at codon 1544 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Edvardsen H et al. Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. Radiat Oncol. 2007 Jul 10;2:25. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2018 | This variant is denoted ATM c.4631A>G at the cDNA level, p.Tyr1544Cys (Y1544C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant has been observed in individuals with breast or lung cancer, but has also been observed in a healthy control subject (Lu 2015, Decker 2017). ATM Tyr1544Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Tyr1544Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 08, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2020 | Variant summary: ATM c.4631A>G (p.Tyr1544Cys) results in a non-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 3.3e-05 in 240942 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4631A>G has been reported in the literature in individuals affected with breast cancer and also in individuals undergoing hereditary cancer testing (Edvardsen_2007, Tung_2014, Schubert_2019, Mu_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrence with another pathogenic variant has been reported (internal sample; NBN c.657_661delACAAA, p.Lys219AsnfsX16) for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1544 of the ATM protein (p.Tyr1544Cys). This variant is present in population databases (rs779718362, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or lung cancer (PMID: 25186627, 26689913, 30426508). ClinVar contains an entry for this variant (Variation ID: 245791). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2022 | The p.Y1544C variant (also known as c.4631A>G), located in coding exon 30 of the ATM gene, results from an A to G substitution at nucleotide position 4631. The tyrosine at codon 1544 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). In another study, This variant was identified in 1/272 Norwegian breast cancer patients and was not observed in 95 cancer-free Norwegian controls or 95 American breast cancer patients (Edvardsen H et al. Radiat Oncol, 2007 Jul;2:25). This alteration was also detected on a 25-gene panel test in a woman diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2023 | This missense variant replaces tyrosine with cysteine at codon 1544 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 17623063, 25186627, 28779002, 29522266, 33471991). However, in two large breast cancer case-control studies, this variant has also been identified in control groups (PMID: 28779002, 33471991). In a case-control study conducted in the UK, this variant was reported in 1/13087 breast cancer cases and 1/5488 controls (PMID: 28779002). In an international case-control meta-analysis, this variant was reported in 2/60464 breast cancer cases and 11/53450 controls (OR=0.161, 95%CI 0.036 to 0.725, p-value=0.009; PMID: 33471991). This variant has also been reported in individuals affected with caecal adenocarcinoma (PMID: 3638722) and metastatic prostate cancer (PMID: 36979741). This variant has been identified in 8/240752 chromosomes in the general population by the Genome Aggregation Database (gnomAD), all of which were found in individuals of European (non-Finnish) ancestry (8/109334 chromosomes). 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. - |
Familial cancer of breast Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 14, 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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 02, 2023 | - - |
ATM-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2024 | The ATM c.4631A>G variant is predicted to result in the amino acid substitution p.Tyr1544Cys. This variant has been reported in individuals with breast or lung cancer (Tung N et al. 2014. PubMed ID: 25186627; Lu C et al. 2015. PubMed ID: 26689913; Schubert S et al. 2019. PubMed ID: 30426508; Hauke J et al. 2018. PubMed ID: 29522266). This variant is reported in 0.0073% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as uncertain significance in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/245791/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of catalytic residue at L1545 (P = 0.0134);Gain of catalytic residue at L1545 (P = 0.0134);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at