rs200432447
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_007194.4(CHEK2):c.1555C>T(p.Arg519*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,588,388 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 Likely pathogenic (★★).
Frequency
Consequence
NM_007194.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000133 AC: 2AN: 150064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000429 AC: 1AN: 232840Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128096
GnomAD4 exome AF: 0.0000111 AC: 16AN: 1438324Hom.: 0 Cov.: 30 AF XY: 0.00000698 AC XY: 5AN XY: 716158
GnomAD4 genome AF: 0.0000133 AC: 2AN: 150064Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1AN XY: 73214
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:6
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This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the CHEK2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 25186627, 25503501, 27751358, 29020732, 29520813, 30287823, 30680046, 32761968). ClinVar contains an entry for this variant (Variation ID: 128064). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 34903604). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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not provided Pathogenic:4
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Nonsense variant predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, prostate, and other cancers (PMID: 25503501, 25186627, 25318351, 32832836, 32761968, 35118230); Published functional studies are inconclusive: demonstrate intermediate impact on phosphorylation compared to wildtype (PMID: 34903604); This variant is associated with the following publications: (PMID: 26681312, 29520813, 12909615, 24879340, 33309985, 36243179, 25503501, 25318351, 27751358, 29020732, 18004398, 29308099, 25186627, 30680046, 30287823, 30293905, 35273153, 32805687, 32832836, 32980694, 32761968, 34204722, 32322110, 32172797, 35118230, 32019277, 36988593, 31650100, 35643632, 38575974, 22419737, 38898688, 34903604) -
The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of the nuclear localization signal that is located within the truncated 25 amino acids (PMID: 24879340 (2014), 22419737 (2012), 12909615 (2003)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32805687 (2020), 32761968 (2020), 30287823 (2018), 25503501 (2015), 25318351 (2014)), ovarian cancer (PMID: 29020732 (2018), prostate cancer (PMID: 29520813 (2018)), and colorectal cancer (PMID: 26681312 (2015)). Experimental studies showed inconclusive results regarding the variant’s impact on protein function (PMID: 34903604 (2021)). The frequency of this variant in the general population, 0.000099 (1/10138 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:4
The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1555. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Zannini L et al. J. Biol. Chem. 2003 Oct;278:42346-51). This mutation has been reported in the literature in breast cancer and prostate cancer cohorts (Yorczyk A et al. Clin. Genet. 2015 Sep;88:278-82; Maxwell K et al. Genet. Med. 2015 Aug;17:630-8; Wu Y et al. Prostate 2018 06;78(8):607-615; Fonfria M et al. J Pers Med 2021 Jun;11(6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant transcript is likely to escape nonsense-mediated decay and expressed as a truncated protein that lacks the functionally important nuclear localization signal (PMID: 12909615, 16798742, 24879340). This variant has been reported in seven individuals affected with breast cancer, including two individuals having a family history of breast or colorectal cancer (PMID: 25503501, 25318351, 30287823; Color internal data) and in an individual affected with ovarian cancer with a family history colorectal cancer (PMID: 29020732). This variant has also been reported individuals affected with uterine cancer (PMID: 30680046) and prostate cancer (PMID: 29520813), and in four unaffected individuals (PMID: 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense codon, resulting in a null variant. This type of variant is a known mechanism of disease. It was rarely reported in the gnomAD population database. This likely pathogenic variant was detected in a 73-year-old Korean female diagnosed with hormone-positive and invasive breast cancer. The patient had a first-degree family member with pancreatic cancer in their 70s. -
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Li-Fraumeni syndrome 2 Pathogenic:1
Criteria applied: PVS1_STR, PS4_MOD, PM2_SUP -
Breast and/or ovarian cancer Pathogenic:1
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Gastric cancer Pathogenic:1
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Familial cancer of breast;C2931456:Familial prostate cancer Pathogenic:1
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Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
PVS1_Strong+PM2_Supporting+PS4 -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-06 in 232840 control chromosomes (gnomAD). c.1555C>T has been reported in the literature in multiple individuals affected with colon cancer, prostate cancer, breast cancer and/or ovarian cancer (Yorczyk_2014, Maxwell_2014, Susswein_2015, Velho_2019, Ryu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (5x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Breast and colorectal cancer, susceptibility to Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at