CHEK2 c.1421G>A, p.Arg474His
NM_007194.4:c.1421G>A
COSMIC ID: COSM4103242
Likely Pathogenic
NM_007194.4:c.1421G>A (R474H) in CHEK2 meets two Moderate criteria (PM2, PM5) and two Supporting criteria (PP3, PP5) with no applicable benign criteria, leading to a final classification of Likely Pathogenic.
ACMG/AMP Criteria Applied
PM2
PM5
PP3
PP5
Genetic Information
Gene & Transcript Details
Gene
CHEK2
Transcript
NM_007194.4
MANE Select
Total Exons
15
Strand
Reverse (−)
Reference Sequence
NC_000022.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007194.3 | Alternative | 15 exons | Reverse |
Variant Details
HGVS Notation
NM_007194.4:c.1421G>A
Protein Change
R474H
Location
Exon 13
(Exon 13 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 474: R474C
Alternate Identifiers
COSM4103242
Variant interpretation based on transcript NM_007194.4
Genome Browser
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HGVS InputNM_007194:c.1421G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00716%
Rare
Highest in Population
African/African American
0.0213%
Low Frequency
Global: 0.00716%
African/African American: 0.0213%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 265178Alt: 19Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00716%, 19/265178 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0213%, 5/23450 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
10 publications
Likely Pathogenic
Based on 20 submitter reviews in ClinVar
Submitter Breakdown
7 LP
12 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (10)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 474 of the CHEK2 protein (p.Arg474His). This variant is present in population databases (rs121908706, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and non-Hodgkin lymphoma (PMID: 25186627, 25452441, 26506619, 30303537, 30333958, 30613976, 31050813, 34903604, 35534704). This variant is also known as p.Arg517His. ClinVar contains an entry for this variant (Variation ID: 126910). 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 affects CHEK2 function (PMID: 31050813, 34903604). 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.
PS3; PS4_SUP
Variant summary: CHEK2 c.1421G>A (p.Arg474His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 233796 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1421G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, or an unspecified hereditary cancer (e.g. Girard_2019, de Oliveira_2022, Kleiblova_2019, Couch_2015, Rizzolo_2019, Brovkina_2018, Bhai_2021, Akcay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <20% of normal kinase activity (Kleiblova_2019, Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 34326862, 34903604, 30333958, 25452441, 30303537, 26506619, 31050813, 30613976, 30374176, 25186627, 35534704). ClinVar contains an entry for this variant (Variation ID: 126910). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Uncertain significance (12 clinical laboratories) and as Likely pathogenic (7 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 474: R474C
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.867
0.867
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Benign:
CADD: 3.18polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: R474H is a missense change, not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no other nucleotide change leading to R474H has been reported as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo status has been documented. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed on R474H. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or prevalence data in affected individuals are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or well‐studied functional domain without benign variation". The evidence for this variant shows: no specific hotspot or domain evidence has been provided. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: MAF = 0.00716% in gnomAD (19/265,178 alleles), which is <0.1%. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: no data on trans configuration with a known pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: R474H is a missense variant with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen". The evidence for this variant shows: a different missense alteration at residue R474 has been reported as pathogenic. Therefore, this criterion is applied at Moderate strength because the novel variant affects the same residue with prior pathogenic missense evidence.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: CHEK2 has both missense and loss-of-function pathogenic mechanisms, and the benign/missense variation rate is not clearly low. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". The evidence for this variant shows: REVEL score = 0.87, exceeding the VCEP threshold of 0.75 for CHEK2, supporting deleterious effect. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no patient phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: ClinVar reports the variant as Likely Pathogenic by 7 clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases". The evidence for this variant shows: MAF = 0.00716%, which is far below the 5% threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF = 0.00716%, which is not greater than expected for CHEK2-related disease. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no data on healthy adult carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function variants cause disease". The evidence for this variant shows: CHEK2 has disease-causing missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". The evidence for this variant shows: no phasing data with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in a repetitive region without a known function". The evidence for this variant shows: R474H is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: computational tools predict deleterious effect (e.g., REVEL = 0.87). Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case data are provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but the evidence is not available to the laboratory". The evidence for this variant shows: ClinVar includes one Likely Benign assertion among conflicting interpretations. Due to conflicting reports, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: R474H is a missense change. Therefore, this criterion is not applied.