rs201762714
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000051.4(ATM):āc.2021A>Gā(p.His674Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. H674Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2021A>G | p.His674Arg | missense_variant | 13/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2021A>G | p.His674Arg | missense_variant | 13/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251404Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135870
GnomAD4 exome AF: 0.000196 AC: 287AN: 1461790Hom.: 1 Cov.: 31 AF XY: 0.000216 AC XY: 157AN XY: 727194
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 26787654, 26689913, 28779002, 27043212, 28873162, 28652578, 31159747, 33471991, 31206626, 32283892, 35264596) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 30, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 07, 2016 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 25, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
not specified Uncertain:1Benign:1
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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 20, 2023 | Variant summary: ATM c.2021A>G (p.His674Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 255894 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. This frequency (0.00085) is somewhat lower than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no clear conclusions about variant significance. However, the variant was also reported in 3/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database), supporting a benign role for the variant. c.2021A>G has been reported in the literature in individuals with a personal and/or family history of breast/ovarian cancer, and other tumor phenotypes (e.g. Young_2015, Tsaousis_2019, Weitzel_2019, Erdm_2020, Guindalini_2022), as well as in controls (e.g. Tavtigian_2009). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 10/60466 cases, but was also found in 10/53461 controls (Dorling_2021, reported through LOVD). A co-occurrence with another pathogenic variant has been reported internally (CHEK2 c.1368dupA, p.Glu457fsX33), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 1Eleven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant VUS (n=8), or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 26, 2023 | - - |
Bilateral breast carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Health System - Franciscan Health care, Mayo Clinic Health System | Sep 25, 2014 | - - |
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 | - - |
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.His674Arg variant was identified in the ATM mutation-screening data from the literature study in 1 of 4798 (freq. 0.0002) control chromosomes from healthy individuals and was not identified in 8224 proband chromosomes from individuals or families with breast cancer (Tavtigian 2009). The variant was also identified in dbSNP (ID: rs201762714) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and four other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 45 of 277138 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5 of 34418 chromosomes (freq: 0.0002), European in 14 of 126640 chromosomes (freq: 0.0001), and South Asian in 26 of 30782 chromosomes (freq: 0.0009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.His674 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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. - |
ATM-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 19, 2024 | 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 06, 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]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at