rs587782441
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_007194.4(CHEK2):c.1012C>T(p.Leu338Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. L338H) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1012C>T | p.Leu338Phe | missense_variant | 10/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1012C>T | p.Leu338Phe | missense_variant | 10/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1455990Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 724756
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2023 | The p.L338F variant (also known as c.1012C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1012. The leucine at codon 338 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In another study, this variant was not detected in 60,466 breast cancer cases and seen in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration behaved as 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 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 09, 2021 | This missense variant replaces leucine with phenylalanine at codon 338 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A yeast-based experimental functional assay demonstrated no impact to CHEK2 DNA damage repair activity (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 | curation | Sema4, Sema4 | Dec 16, 2021 | - - |
Familial cancer of breast Uncertain:3
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 | Invitae | Nov 16, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 338 of the CHEK2 protein (p.Leu338Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with features of hereditary cancer (PMID: 31159747, 34326862). ClinVar contains an entry for this variant (Variation ID: 142406). 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. Experimental studies have shown that this missense change does not substantially affect 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 | Jun 16, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2018 | This variant is denoted CHEK2 c.1012C>T at the cDNA level, p.Leu338Phe (L338F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu338Phe was not observed in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Leu338Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at