22-28734664-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_007194.4(CHEK2):c.58C>T(p.Gln20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,966 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007194.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152082Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000141 AC: 35AN: 247462Hom.: 0 AF XY: 0.000201 AC XY: 27AN XY: 134030
GnomAD4 exome AF: 0.0000664 AC: 97AN: 1461766Hom.: 0 Cov.: 33 AF XY: 0.0000935 AC XY: 68AN XY: 727180
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152200Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74416
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:7
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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A pathogenic mutation was detected in the CHEK2 gene (c.58C>T).This sequence change creates a premature translational stop signal (p.Gln20*) in the CHEK2 gene. This variant is expected to result in an absent or non-functional protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant Not observed at a significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887) classified as pathogenic with no conflict . For these reasons, this variant has been classified as Pathogenic. -
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This sequence change creates a premature translational stop signal (p.Gln20*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs536907995, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887). For these reasons, this variant has been classified as Pathogenic. -
The CHEK2 constitutional genetic variant leads to a premature truncation of the protein at 20 amino acids leading to loss of the domains crucial for the interaction of proteins like ATM/BRCA2 which are master regulator of the DNA damage repair pathways. The outcome of this mutation could be observed in various cancers specially breast and ovarian cancers, which also corroborates with the familial breast cancer history of the proband, although the proband is yet asymptomatic. Hence, keeping in view the functional effect the variant has been classified pathogenic. -
not provided Pathogenic:6
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This nonsense variant is predicted to cause the premature termination of CHEK2 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMIDs: 26023681 (2015), 27510020 (2016), 28724667 (2017), 32658311 (2021), and 32885271 (2021)). Based on the available information, this variant is classified as likely pathogenic. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history of CHEK2-related cancers in published literature (Foley 2015, Baloch 2016, Scarpa 2017, Sun 2017, Fan 2018, Akcay 2020); This variant is associated with the following publications: (PMID: 26023681, 28724667, 28199314, 27039729, 24728327, 27510020, 29356917, 28779002, 29922827, 28553140, 32658311) -
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Hereditary cancer-predisposing syndrome Pathogenic:3
This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 27039729, 28724667, 32658311, 32885271), an individual affected with ovarian cancer (PMID: 32885271) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000005). This variant has also been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic variant in the BRCA2 gene (PMID: 26023681). This variant is found at a high frequency in the South Asian population (0.1145%, 35/30544 chromosomes) by the Genome Aggregation Database (gnomAD), suggesting its penetrance may be reduced relative to other pathogenic CHEK2 alleles. Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic -
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The p.Q20* pathogenic mutation (also known as c.58C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 58. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration was detected in conjunction with a pathogenic BRCA2 mutation in an individual diagnosed with breast cancer at ages 37 and 61 and ovarian cancer at age 56 (Foley SB et al. EBioMedicine. 2015 Jan;2:74-81). This alteration has also been observed in breast cancer cohorts (Baloch AH et al. Asian Pac. J. Cancer Prev. 2016;17:1089-92; Sun J et al. Clin Cancer Res 2017 Oct;23(20):6113-6119). In one case-control study, this alteration was not identified in 13087 breast cancer cases but was seen in 1/5488 control individuals in the United Kingdom; of note, study subjects were under the age of 55 years (Decker B et al. J Med Genet 2017 11;54(11):732-741). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Li-Fraumeni syndrome 2 Pathogenic:1
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Familial cancer of breast;C0585442:Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
PM2+PS4_Supporting+PVS1 -
Familial ovarian cancer Pathogenic:1
The CHEK2 p.Gln20* variant was identified in 2 of 858 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Baloch 2016, Foley 2014). The variant was also identified in dbSNP (ID: rs536907995) as "With Pathogenic allele", and in ClinVar (classified as likely pathogenic by GeneDx, Color Genomics; as pathogenic by Invitae, Counsyl). The variant was not identified in the Zhejiang University database. The variant was identified in control databases in 36 of 242162 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the South Asian population in 36 of 30708 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The c.58C>T variant leads to a premature stop codon at position 20 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in CHEK2-associated cancers and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Breast carcinoma Pathogenic:1
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Inherited breast cancer and ovarian cancer Uncertain:1
PVS1_Moderate -
not specified Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at