rs749471737
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):c.2945G>A(p.Arg982His) variant causes a missense change. The variant allele was found at a frequency of 0.00000995 in 1,608,774 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. R982C) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2945G>A | p.Arg982His | missense_variant | 20/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2945G>A | p.Arg982His | missense_variant | 20/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000679 AC: 1AN: 147200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251002Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135654
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461574Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11AN XY: 727090
GnomAD4 genome ? AF: 0.00000679 AC: 1AN: 147200Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1AN XY: 71366
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:5
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 29, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2023 | This missense variant replaces arginine with histidine at codon 982 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, colorectal cancer or an unspecified cancer (PMID: 28135145, 28873162, 33606809). This variant has been identified in 2/251002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 30, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2023 | The p.R982H variant (also known as c.2945G>A), located in coding exon 19 of the ATM gene, results from a G to A substitution at nucleotide position 2945. The arginine at codon 982 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in 3/224 unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). It has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535) as well as in an individual diagnosed with colorectal cancer (Yurgelun MB et al. J Clin Oncol. 2017 Apr;35:1086-1095). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ataxia-telangiectasia syndrome Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 02, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jun 26, 2023 | The ATM c.2945G>A (p.Arg982His) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). 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 breast cancer (PMID: 33606809) and colorectal cancer (PMID: 28135145). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast or other cancers (Mandelker et al., 2017; Yurgelun et al., 2017; Tsaousis et al., 2019; Bhai et al., 2021; Sandoval et al., 2021); This variant is associated with the following publications: (PMID: 28135145, 28873162, 28652578, 31159747, 19781682, 34326862, 33606809) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at