rs3218670
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
The NM_000051.4(ATM):c.6101G>A(p.Arg2034Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2034P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6101G>A | p.Arg2034Gln | missense_variant | 42/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6101G>A | p.Arg2034Gln | missense_variant | 42/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000143 AC: 36AN: 251356Hom.: 0 AF XY: 0.000191 AC XY: 26AN XY: 135848
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64AN XY: 727194
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74434
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 08, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 24, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2023 | 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. - |
Familial cancer of breast Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 09, 2023 | 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 | MGZ Medical Genetics Center | Nov 30, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 33471991, 23532176, 33941849, 22529920, 24359602, 30287823, 28779002, 30150316, 28256603, 26580448, 29706348, 32068069, 32980694) - |
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.Arg2034Gln variant was identified in the literature in a pooled case control study of 8224 breast cases and 4798 control cases and was identified in 1 control case (Tavtigian 2009). The variant was identified in the following databases: dbSNP (ID: rs3218670) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and Color Genomics Inc.), Clinvitae (3x), and was not identified in the COGR, Cosmic, MutDB, LOVD 3.0. The variant was also identified in control databases in 37 of 277100 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Latino in 1 of 34410 chromosomes (freq: 0.00003), European Non-Finnish in 3 of 126644 chromosomes (freq: 0.00002), East Asian in 14 of 18836 chromosomes (freq: 0.0007), Finnish in 1 of 25794 chromosomes (freq: 0.00004), and South Asian in 17 of 30776 chromosomes (freq: 0.0006); it was not observed in the Other and Ashkenazi Jewish populations. The p.Arg2034 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the Gln variant impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Ataxia-telangiectasia syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at