rs142358238
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_000051.4(ATM):c.320G>A(p.Cys107Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,612,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. C107R) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.320G>A | p.Cys107Tyr | missense_variant | 4/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.320G>A | p.Cys107Tyr | missense_variant | 4/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000561 AC: 85AN: 151400Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000164 AC: 41AN: 250714Hom.: 0 AF XY: 0.0000959 AC XY: 13AN XY: 135560
GnomAD4 exome AF: 0.0000773 AC: 113AN: 1460926Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44AN XY: 726764
GnomAD4 genome ? AF: 0.000555 AC: 84AN: 151468Hom.: 0 Cov.: 33 AF XY: 0.000528 AC XY: 39AN XY: 73930
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 29, 2015 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 11, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 11, 2019 | 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. - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2017 | This variant is denoted ATM c.320G>A at the cDNA level, p.Cys107Tyr (C107Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in the compound heterozygous state with a nonsense variant in one individual with Ataxia-telangiectasia (A-T), whose diagnosis was confirmed by clinical observation and radiation sensitivity testing (Bernstein 2003). This variant was also observed in at least two individuals undergoing hereditary cancer testing (Yorczyk 2014, Yurgelun 2015), and in at least one individual with acute myeloid leukemia (Lu 2015). Hirsch et al. (2008) did not identify ATM Cys107Tyr in a series of 31 African-American individuals with breast cancer, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 2/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Cys107Tyr was observed at an allele frequency of 0.21% in individuals of African ancestry 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 Cys107Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 05, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 22, 2023 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2017 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 20, 2023 | Variant summary: ATM c.320G>A (p.Cys107Tyr) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 250912 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.320G>A has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Bernstein_2003), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), an unaffected control of African American ancestry (Hirsch_2008), a patient undergoing multigene panel testing for cancer (Yorczyk_2015), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), a patient with AML in the TGCA cohort (Lu_2015), a cerebellar ataxia patient (Coutelier_2018), breast cancer cases and controls (Weitzel_2019, Eygelaar_2022, Guindalini_2022) and in PDAC patients (Zimmermann_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. Additionally, the variant was found to occur in eleven women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and seven ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over six years of evaluations performed at our laboratory spanning the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 09, 2022 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
ATM-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 01, 2024 | The ATM c.320G>A variant is predicted to result in the amino acid substitution p.Cys107Tyr. This variant has been reported with a nonsense variant in the compound heterozygous state in an individual with ataxia telangiectasia (Bernstein et al. 2003. PubMed ID: 12673797). It has also been observed in an individual with acute myeloid leukemia (Lu et al. 2015. PubMed ID: 26689913, supplementary data 12), and in another individual with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, supplemental table 2). However, it has also been observed in four individuals with breast cancer (Eygelaar et al. 2022. PubMed ID: 35039564; Table S3, Guindalini et al. 2022. PubMed ID: 35264596) and found in a control individual from a breast cancer study (Hirsch et al. 2008. PubMed ID: 17333338). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127368/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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.Cys107Tyr variant was identified in 4 of 36,874 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia tenlangiectasia, acute myeloid leukemia, Lynch Syndrome or breast cancer and was present in 3 of 11,166 control chromosomes (frequency: 0.0003) from healthy individuals (Bernstein 2003, Lu 2015, Yurgelun 2015, Hirsch 2008, Decker 2017). The variant was identified in dbSNP (rs142358238) as “with other allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx, Counsyl and 5 other submitters; and as likely benign by Ambry Genetics and Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 60 of 281,758 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 53 of 24,862 chromosomes (freq: 0.002), Latino in 6 of 35,344 chromosomes (freq: 0.0002), and South Asian in 1 of 30,544 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European or Other populations. This variant was identified in the compound heterozygous state in an individual with ataxia telangiectasia with a co-occurring, pathogenic ATM variant (c.7327C>T, p.Arg2443*; Bernstein 2003). The p.Cys107 residue is conserved in mammals but not in more distantly related organisms, although four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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. - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 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 | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at