rs121908704
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_007194.4(CHEK2):c.1201A>G(p.Thr401Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T401T) has been classified as Benign.
Frequency
Consequence
NM_007194.4 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1201A>G | p.Thr401Ala | missense_variant | 11/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1201A>G | p.Thr401Ala | missense_variant | 11/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250994Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135708
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461540Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727098
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 401 of the CHEK2 protein (p.Thr401Ala). This variant is present in population databases (rs121908704, gnomAD 0.004%). This missense change has been observed in individual(s) with non-Hodgkin lymphoma, and breast cancer (PMID: 26506619, 30851065). ClinVar contains an entry for this variant (Variation ID: 126908). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 25, 2023 | - - |
not provided Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
not provided, no classification provided | literature only | Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2020 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with non-Hodgkin lymphoma (Havranek 2015); Published functional studies are inconclusive: intermediate DNA damage response in in vivo yeast-based assays (Delimitsou 2019); This variant is associated with the following publications: (PMID: 26506619, 30851065) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 12, 2021 | This missense variant replaces threonine with alanine at codon 401 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant to result in partial loss of CHEK2 function (PMID: 30851065). This variant has been reported in an individual affected with non-Hodgkin lymphoma (PMID: 26506619). This variant has been identified in 4/250994 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 | Mar 02, 2023 | The p.T401A variant (also known as c.1201A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1201. The threonine at codon 401 is replaced by alanine, an amino acid with similar properties. This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at