11-108294934-A-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):āc.4784A>Gā(p.Asn1595Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4784A>G | p.Asn1595Ser | missense_variant | Exon 32 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251242Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135786
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461492Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727070
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
This missense variant replaces asparagine with serine at codon 1595 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. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 20305132, 31159747). This variant has been identified in 1/251242 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. -
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The p.N1595S variant (also known as c.4784A>G), located in coding exon 31 of the ATM gene, results from an A to G substitution at nucleotide position 4784. The asparagine at codon 1595 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported as a variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing multigene panel testing for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535). This alteration was also identified in 1/2105 women with invasive breast cancer who were tested for variants in the ATM gene (Bernstein JL et al. J Natl Cancer Inst 2010 Apr;102(7):475-83). 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. -
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 an individual with contralateral breast cancer and absent in controls (Bernstein et al., 2010); This variant is associated with the following publications: (PMID: 31159747, 20305132) -
Variant summary: The ATM c.4784A>G (p.Asn1595Ser) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a small size and polar Serine (S) located outside of known functional domains (InterPro, Pfam). 3/3 in silico tools predict a benign outcome for this substitution (SNPs&GO and Mutation taster not captured due to low reliability index). This variant was found in 1/121324 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). To our knowledge, the variant has not been reported in affected patients with strong evidence for causality and studies assessing the impact the variant may have on the function of ATM protein have not been published at the time of classification either. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
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Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at