11-108325447-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):āc.6710A>Cā(p.Lys2237Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2237R) has been classified as Uncertain significance.
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.6710A>C | p.Lys2237Thr | missense_variant | 46/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6710A>C | p.Lys2237Thr | missense_variant | 46/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251094Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135712
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461630Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727124
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74306
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 28, 2021 | This missense variant replaces lysine with threonine at codon 2237 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251094 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 | Jun 20, 2022 | The p.K2237T variant (also known as c.6710A>C), located in coding exon 45 of the ATM gene, results from an A to C substitution at nucleotide position 6710. The lysine at codon 2237 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). In a large study of familial breast cancer families, this variant was identified in 0/443 cases and 1/521 controls (Renwick A et al. Nat Genet, 2006 Aug;38:873-5). 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. - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 2237 of the ATM protein (p.Lys2237Thr). This variant is present in population databases (rs35118109, gnomAD 0.0009%). 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: 524419). 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 disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at