chr22-28696911-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_007194.4(CHEK2):c.1085G>A(p.Cys362Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C362R) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1085G>A | p.Cys362Tyr | missense_variant | 10/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1085G>A | p.Cys362Tyr | missense_variant | 10/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251248Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135818
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457350Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3AN XY: 725328
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 218157). This variant is also known as c.1214G>A (p.Cys405Tyr). This missense change has been observed in individual(s) with a personal history of breast cancer, thyroid cancer, and bladder cancer (PMID: 26328243). This variant is present in population databases (rs767306337, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 362 of the CHEK2 protein (p.Cys362Tyr). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2021 | The p.C362Y variant (also known as c.1085G>A), located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1085. The cysteine at codon 362 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, reported as NM_001005735.1:c.1214G>A, has been identified in a proband with a personal history of triple negative breast cancer, thyroid cancer and bladder cancer (Ollier M et al. Am J Cancer Res, 2015 Jun;5:2113-26). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Triple-negative breast cancer Other:1
association, no assertion criteria provided | case-control | Molecular Oncology Laboratory, Centre Jean Perrin | Feb 26, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at