11-108244102-G-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.646G>T(p.Ala216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,558 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 Uncertain significance (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.646G>T | p.Ala216Ser | missense_variant | Exon 6 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 151910Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251182Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461530Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 727058
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152028Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74306
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
- -
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 216 of the ATM protein (p.Ala216Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 141750). 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%. 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. -
not provided Uncertain:2
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 breast cancer or leukemia, but also in healthy controls (PMID: 19781682, 26689913, 28779002, 33471991); This variant is associated with the following publications: (PMID: 28779002, 11443540, 19781682, 22529920, 26689913, 27720647, 15026370, 33471991) -
- -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.A216S variant (also known as c.646G>T), located in coding exon 5 of the ATM gene, results from a G to T substitution at nucleotide position 646. The alanine at codon 216 is replaced by serine, an amino acid with similar properties. This variant has been identified in numerous disease cohorts as well as unaffected control groups across studies (Thorstenson YR et al. Am. J. Hum. Genet. 2001 Aug;69:396-412; Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker B et al. J Med Genet, 2017 11;54:732-741; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is 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. -
This missense variant replaces alanine with serine at codon 216 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 one individual each affected with breast cancer (PMID: 28779002) and leukemia (PMID: 26689913). This variant also has been reported in individuals without cancer (PMID: 19781682; FLOSSIES database) or has no obvious genetic disease (PMID: 11443540). This variant has been identified in 4/246010 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. -
not specified Uncertain:1
Variant summary: ATM c.646G>T (p.Ala216Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251182 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.646G>T in individuals affected with ATM-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 141750). Based on the evidence outlined above, the variant was classified as uncertain significance. -
ATM-related disorder Uncertain:1
The ATM c.646G>T variant is predicted to result in the amino acid substitution p.Ala216Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141750/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial cancer of breast Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at