rs745773225
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.928A>G(p.Ser310Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,612,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. S310N) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.928A>G | p.Ser310Gly | missense_variant | 8/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.928A>G | p.Ser310Gly | missense_variant | 8/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250870Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135704
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1459780Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 726252
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Ser310Gly variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs745773225) as “With Uncertain significance allele”, and in ClinVar (4x as uncertain significance by Invitae, Ambry Genetics, GeneDx, Color Genomics). The variant was identified in control databases in 4 of 245900 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 4 of 30778 chromosomes (freq: 0.00013). It was not observed in the African, “Other”, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ser310 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 03, 2023 | The p.S310G variant (also known as c.928A>G), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 928. The serine at codon 310 is replaced by glycine, an amino acid with similar properties. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 04, 2024 | This missense variant replaces serine with glycine at codon 310 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large international case-control meta-analysis, this variant was reported in 1/60465 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been identified in 4/250870 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. - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.928A>G (p.Ser310Gly) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ser310Gly variant is novel (not in any individuals) in 1000 Genomes. The amino acid Ser at position 310 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved across species. The amino acid change p.Ser310Gly in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at