chr11-108244805-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000051.4(ATM):c.680C>T(p.Ser227Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S227S) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.680C>T | p.Ser227Leu | missense_variant | Exon 7 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152026Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251126 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461392Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727000 show subpopulations
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152026Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74242 show subpopulations
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
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This missense variant replaces serine with leucine at codon 227 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 observed in individuals affected with breast cancer (Color Health internal data), prostate cancer (PMID: 33436325), glioblastoma multiforme (PMID: 26689913), as well as in an individual referred for hereditary cancer genetic testing (PMID: 31159747). This variant has been identified in 1/251126 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. -
The p.S227L variant (also known as c.680C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 680. The serine at codon 227 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration has 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). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
not provided Pathogenic:1Uncertain:1
RNA studies demonstrate a damaging effect: aberrant splicing leading to out-of-frame exon skipping, resulting in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (External communication with an outside laboratory); Observed in individuals with prostate cancer, glioblastoma, or premature ovarian insuffiency (PMID: 33436325, 26689913, 38649916); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 38649916, 31159747, 26689913, 33436325) -
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Familial cancer of breast Pathogenic:1Uncertain:1
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 227 of the ATM protein (p.Ser227Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (gnomAD). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer, or prostate cancer (PMID: 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 485170). In silico analysis supports that this missense variant does not alter protein structure/function . 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. Pathogenic/likely pathogenic mutations in the ATM gene cause susceptibility to breast cancer (OMIM 114480). -
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -
Ataxia-telangiectasia syndrome Pathogenic:1
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 227 of the ATM protein (p.Ser227Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs762998620, gnomAD 0.007%). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer, or prostate cancer (PMID: 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 485170). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Studies have shown that this missense change results in skipping of exon 7, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -
not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at