rs786203765
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate
The NM_000051.4(ATM):c.5938G>A(p.Gly1980Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000097 in 1,443,276 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1980?) has been classified as Pathogenic.
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.5938G>A | p.Gly1980Arg | missense_variant | 40/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5938G>A | p.Gly1980Arg | missense_variant | 40/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251186Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135822
GnomAD4 exome AF: 0.00000970 AC: 14AN: 1443276Hom.: 0 Cov.: 29 AF XY: 0.00000834 AC XY: 6AN XY: 719096
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 21, 2022 | This missense variant replaces glycine with arginine at codon 1980 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. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has also been reported in an individual affected with multiple adenomatous polyps (PMID: 25938944). This variant has been identified in 2/251186 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 | Ambry Genetics | May 05, 2023 | The p.G1980R variant (also known as c.5938G>A), located in coding exon 39 of the ATM gene, results from a G to A substitution at nucleotide position 5938. The glycine at codon 1980 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in 1/51 patients with multiple colorectal adenomas who underwent whole exome sequencing (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). 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. - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1980 of the ATM protein (p.Gly1980Arg). This variant is present in population databases (rs786203765, gnomAD 0.002%). This missense change has been observed in individual(s) with colon polyps and with breast cancer and/or ovarian cancer (PMID: 25938944, 29522266). ClinVar contains an entry for this variant (Variation ID: 187479). 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 tolerated. 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 breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Oct 02, 2018 | This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1980 in the ATM protein. This is a rare variant, and has been observed in the gnomAD database at a frequency of 0.00001792 (2/111586 alleles). The variant has additionally been observed in a BRCA1/2-negative breast cancer case (PMID 29522266), a breast cancer case identified in the Breast Cancer Family Registry (PMID 21787400), and a case with multiple adenomatous polyps (PMID 25938944). This variant alters an amino acid residue found within the FAT (FRAP-ATM-TRRAP) domain of the ATM protein. Bioinformatic tools queried are inconsistent in their predictions of the pathogenicity of this variant, and the glycine residue at this position in the ATM protein is poorly conserved among mammalian species. There are no functional studies determining the effect of this variant on protein structure and function, to our knowledge. Though there are no published reports strongly linking this variant to disease to date, there is insufficient evidence at this time to fully assess if this variant is pathogenic or benign. Thus, it is a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at