chr22-28695810-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_007194.4(CHEK2):c.1159A>G(p.Thr387Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T387I) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1159A>G | p.Thr387Ala | missense_variant | 11/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1159A>G | p.Thr387Ala | missense_variant | 11/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251032Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135714
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | Experimental studies have shown that this missense change affects CHEK2 function (PMID: 11390408, 12805407, 16835864, 20713355). 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. This variant disrupts the serine/threonine kinase domain of the CHEK2 protein, which is essential for protein function (PMID: 30264118, 31843900, 29785007). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 460788). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 29945567). This variant is present in population databases (rs771387164, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 387 of the CHEK2 protein (p.Thr387Ala). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 28, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20713355, 16835864, 11390408]. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2024 | The p.T387A variant (also known as c.1159A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1159. The threonine at codon 387 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of pancreatic cancer patients unselected for family history (Young EL et al. BMC Cancer. 2018 Jun;18:697). This alteration is located in the activation loop of the CHEK2 kinase domain, and has been shown to result in abolished CHEK2 kinase activity (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at