chr22-28696964-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4
The NM_007194.4(CHEK2):āc.1032A>Gā(p.Ile344Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. I344T) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1032A>G | p.Ile344Met | missense_variant | 10/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1032A>G | p.Ile344Met | missense_variant | 10/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251208Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135786
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460396Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4AN XY: 726602
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74466
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2022 | 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 individuals with breast cancer as well as in unaffected controls in published literature (Momozawa 2018).; This variant is associated with the following publications: (PMID: 30287823, 22419737, 19782031) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 08, 2022 | The frequency of this variant in the general population, 0.00035 (7/19946 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer as well as in several healthy controls (PMID: 30287823 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2023 | The p.I344M variant (also known as c.1032A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1032. The isoleucine at codon 344 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported with a carrier frequency of 0.00057 in 7,051 unselected breast cancer patients and 0.00036 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been reported in 1/416 papillary thyroid carcinoma patients and 0/100 healthy controls (Shen CT et al. Endocrine, 2019 06;64:622-631). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 12, 2018 | - - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 344 of the CHEK2 protein (p.Ile344Met). This variant is present in population databases (rs202051128, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 232564). 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