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Variant interpretation report

CHEK2 c.1604G>A, p.(Arg535His)

NM_007194.4:c.1604G>A NP_009125.1:p.(Arg535His) View identifiers
Classification
Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About CHEK2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen CHEK2 VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple independent lines of computational evidence predict no damaging effect: REVEL score 0.046 (below the default 0.5 pathogenicity threshold), BayesDel score -0.342 (negative, strongly supporting benign), SpliceAI max delta 0.00 (no predicted splice alteration), and in silico tools from PMID:30851065 (SIFT: Tolerated, Align GVGD: C0, MutationTaster: Polymorphism). Four independent predictors converge on a benign interpretation.

Recorded classification: Not classified

No source classification-combination explanation was recorded.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
146 / 1,594,044 alleles

gnomAD v4.1: 146 / 1,594,044 alleles. Recorded AF 9.15909e-05. Recorded homozygote count 2.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00023782; MAF= 0.02378%, 63/264906 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00201134; MAF= 0.20113%, 61/30328 alleles, homozygotes = 1); grpmax FAF= 0.00160659.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0004508566275924256, 8/17744 alleles, homozygotes = 0).

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

ClinVar submissions
15 reported laboratory submissions

8 Likely benign · 6 Uncertain significance · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

In progress — evidence not uploaded yet.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

For specialists

Technical detail

ACMG/AMP criteria under ClinGen CHEK2 VCEP v1.0, with the data and sources behind each one.

26 criteria with recorded statuses: 1 met · 13 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Met Not met Not assessed Not applicable

NM_007194.4:c.1604G>A (p.Arg535His) is a missense variant in CHEK2 located in the C-terminal region of the protein, outside the kinase and FHA domains.

Multiple independent computational predictors (REVEL 0.046, BayesDel -0.342, SpliceAI delta 0.00, SIFT Tolerated, Align GVGD C0, MutationTaster Polymorphism) converge on a benign interpretation, satisfying BP4 at supporting benign strength.

Direct functional assessment in a yeast-based assay (Delimitsou et al. 2019, PMID:30851065) characterized this variant as benign (wild-type-like function), consistent with the computational predictions.

The variant is present in gnomAD population databases (v2.1: 63/264,906 alleles, AF=0.024%, grpmax FAF=0.16%, 1 homozygote; v4.1: 146/1,594,044 alleles, AF=0.0092%, grpmax FAF=0.11%, 2 homozygotes) with highest frequency in the South Asian subpopulation (0.20% v2.1).

In ClinVar (VariationID 128067), this variant has received a mixed classification: Likely benign by 8 clinical laboratories, Uncertain significance by 6, and Benign by 1. Review status is single-submitter (1-star) rather than expert panel.

No pathogenic ACMG/AMP criteria are met. No benign criteria are met beyond BP4 (supporting benign). The evidence is insufficient for a definitive benign classification; the variant remains a variant of uncertain significance (VUS), leaning benign based on computational and functional data.

Met · 1

BP4 SupportingMultiple independent lines of computational evidence predict no damaging effect: REVEL score 0.046 (below the default 0.5 pathogenicity threshold), BayesDel score -0.342 (negative, strongly supporting benign), SpliceAI max delta 0.00 (no predicted splice alteration), and in silico tools from PMID:30851065 (SIFT: Tolerated, Align GVGD: C0, MutationTaster: Polymorphism). Four independent predictors converge on a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.046 (threshold for pathogenicity is >0.5)
  • BayesDel score -0.342 (negative scores support benign)
  • SpliceAI max delta 0.00 (no splicing impact)
  • SIFT Tolerated
  • Align GVGD C0
  • MutationTaster Polymorphism (0.999)
Sources

Not met · 13 · evaluated, threshold not reached

PS3 The variant was directly tested in a yeast-based functional assay (PMID:30851065) and categorized as BENIGN (wild-type-like function). In silico predictions are concordant: SIFT tolerated, Align GVGD C0, MutationTaster polymorphism (0.999). PolyPhen-2 predicted probably damaging (discordant). No other functional studies tested this variant. A benign functional result does not support PS3; the evidence is more consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • Yeast-based functional assay (Delimitsou et al. 2019): variant c.1604G>A p.(Arg535His) characterized as Benign (functional
  • wild-type-like growth after MMS-induced DNA damage)
  • In vivo result: normalized median above 0.70 and normalized standardized difference of means above 0.30
  • consistent with wild-type function
Still missing
  • No functional data in human cell lines for this specific variant
  • PolyPhen-2 prediction (probably damaging) is discordant with the yeast functional result
Sources
PM1 Residue Arg535 is located in the C-terminal region outside the characterized kinase domain (aa 220-486) and FHA domain (aa 115-175). The domain annotation in PMID:30851065 lists it as '-' (no specific functional domain). Cancerhotspots.org does not identify this residue as a significant hotspot. The C-terminal region including the NLS (aa 515-522) is not a well-established mutational hotspot. Details ▾Hide ▴
Evidence considered
  • Arg535 is in the C-terminal region beyond the kinase domain
  • domain annotated as '-' in Delimitsou et al. 2019 Table 1
  • Not a statistically significant hotspot per cancerhotspots.org
Sources
PM2 This variant is present in gnomAD v2.1 at a global frequency of 0.024% (63/264,906 alleles, 1 homozygote) and v4.1 at 0.0092% (146/1,594,044 alleles, 2 homozygotes). The grpmax filtering allele frequency is 0.16% (v2.1) and 0.11% (v4.1), both exceeding the 0.1% threshold for PM2. The highest subpopulation frequency is in South Asian (v2.1 AF=0.20%, v4.1 AF=0.13%). Presence in population databases with a homozygous individual precludes application of PM2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: total AF=0.0238% (63/264
  • 906)
  • SAS AF=0.20% (61/30
  • 328)
  • 1 homozygote
  • grpmax FAF=0.16%
  • gnomAD v4.1: total AF=0.0092% (146/1
  • 594
  • 044)
  • SAS AF=0.13% (119/90
  • 844)
  • 2 homozygotes
  • grpmax FAF=0.11%
Sources
PP2 CHEK2 has a high rate of benign missense variation (1.87% missense variants in gnomAD). The gene does not have a low rate of benign missense variation, which is a prerequisite for PP2. Details ▾Hide ▴
Evidence considered
  • High rate of benign missense variation in CHEK2
  • 1.87% of gnomAD alleles carry missense CHEK2 variants per Stolarova et al. 2023
Sources
PP3 Computational evidence supports a benign interpretation. REVEL score is 0.046 (below the 0.5 threshold for pathogenicity). BayesDel score is -0.342 (negative, supporting benign). SpliceAI max delta is 0.00 (no predicted splice impact). Multiple in silico tools predict no damaging effect. The yeast functional assay (PMID:30851065) also found the variant to be benign. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.046 (benign range)
  • BayesDel score -0.342 (benign range)
  • SpliceAI max delta 0.00 (no splice impact)
  • In silico in PMID:30851065: SIFT Tolerated
  • Align GVGD C0
  • MutationTaster Polymorphism (0.999)
Sources
PP5 ClinVar classification is 'Likely benign' (8 clinical labs) with 'Uncertain significance' (6 labs) and 'Benign' (1 lab). Review status is 'criteria provided, single submitter' (1-star). PP5 requires a reputable source (3-star expert panel) classifying the variant as pathogenic. The ClinVar review status is single-submitter, not expert panel level. Additionally, the predominant classification is benign-leaning, which would support BP6 rather than PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 128067: classified as Likely benign by majority (8 LB
  • 6 VUS
  • 1 B)
  • Review status: criteria provided
  • single submitter (1-star) — not expert panel review
Sources
BA1 The highest population allele frequency is 0.20% in the South Asian subpopulation (gnomAD v2.1), which is well below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 SAS AF=0.20% (61/30
  • 328)
  • gnomAD v4.1 SAS AF=0.13% (119/90
  • 844)
Sources
BS1 The global allele frequency is 0.024% (v2.1) and 0.0092% (v4.1), both below the 0.3% threshold for BS1. The highest subpopulation frequency in South Asians (0.20% v2.1) also remains below the BS1 cutoff. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: global AF=0.024%
  • highest subpop SAS=0.20%
  • gnomAD v4.1: global AF=0.0092%
  • highest subpop SAS=0.13%
Sources
BS2 Only 1 homozygous individual is observed in gnomAD v2.1 (in the South Asian population). BS2 generally requires observation in multiple healthy adult homozygous individuals for a fully penetrant dominant disorder. A single homozygote is not sufficient to meet BS2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1 homozygous individual in South Asian population (61/30
  • 328 alleles
  • 1 hom)
  • gnomAD v4.1: 2 homozygous individuals in South Asian population (119/90
  • 844 alleles
  • 2 hom)
Sources
BS3 A single yeast-based functional study (PMID:30851065) characterized this variant as benign. While this is direct functional evidence of no damaging effect, BS3 requires 'well-established' functional studies (typically replicated in multiple independent studies or using multiple orthogonal assays). A single yeast assay, with one discordant in silico prediction (PolyPhen-2: probably damaging), does not rise to the level of 'well-established.' The functional data is considered supportive but does not independently meet BS3. Details ▾Hide ▴
Evidence considered
  • PMID:30851065: yeast functional assay found c.1604G>A p.(Arg535His) to be Benign (functional)
  • Single study in a yeast model
  • no replication in human cell lines
Still missing
  • No functional data in human cell lines
  • discordant PolyPhen-2 prediction (probably damaging)
Sources
BP2 No evidence of co-occurrence with a known pathogenic variant in trans for a fully penetrant dominant disorder. No data on co-occurrence in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
  • No co-occurrence data available
BP5 No evidence that this variant was found in a case with an alternate molecular basis for disease. BP5 requires identification of an alternate pathogenic variant that explains the phenotype. Details ▾Hide ▴

No further detail was recorded.

BP6 ClinVar review status is 'criteria provided, single submitter' (1-star), not expert panel (3-star) review. Per ClinGen CSPEC guidance, only 3-star expert panel classifications trigger automatic PP5/BP6 application. The overall ClinVar classification is 'Likely benign' but the review status does not meet the threshold for BP6. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 128067: Likely benign (8 labs)
  • Uncertain significance (6 labs)
  • Benign (1 lab)
  • Review status: criteria provided
  • single submitter (1-star) — not expert panel
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant; not a null variant (nonsense, frameshift, or canonical splice). PVS1 variant assessment bucket is 'other'. Does not qualify for PVS1 under generic or VCEP framework. Details ▾Hide ▴
Evidence considered
  • Missense substitution NM_007194.4:c.1604G>A (p.Arg535His) in exon 15. CHEK2 loss-of-function mechanism is supported
  • but this variant type falls outside PVS1 null-variant buckets (PMC6185798).
Sources
pvs1_gene_contextpvs1_variant_assessment
PS1 N/ANo prior classification establishing this same amino acid change (p.Arg535His) as pathogenic at another nucleotide position exists. PS1 requires a different nucleotide change resulting in the same amino acid alteration that has been previously classified as pathogenic. Details ▾Hide ▴

No further detail was recorded.

PS2 N/ANo de novo data reported for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴

No further detail was recorded.

PS4 N/ANo case-control data demonstrating statistically significant enrichment of this variant in affected individuals versus controls. PS4 requires disease-specific case-control data for the variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator variants with established pathogenic classification were identified. PM5 candidate collection was unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Sources
pm5_candidates
PM6 N/ANo de novo data reported for this variant. PM6 requires confirmed de novo occurrence without maternity/paternity confirmation (supporting) or with it (moderate). Details ▾Hide ▴

No further detail was recorded.

PP1 N/ANo segregation data available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴

No further detail was recorded.

PP4 N/ANo phenotype specificity data available. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴

No further detail was recorded.

BS4 N/ANo segregation data available. BS4 requires lack of segregation with disease in multiple affected family members. Details ▾Hide ▴

No further detail was recorded.

BP1 N/AThis is a missense variant, not a truncating variant in a gene where only truncating variants cause disease. BP1 applies specifically to missense variants in genes where truncation is the only known pathogenic mechanism. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant (c.1604G>A) is a missense substitution resulting in p.Arg535His. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ANo established pathogenic variant at this codon (Arg535) has been identified as a comparator. The ClinVar submission referenced in criterion_lead does not establish PS5. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CHEK2
Transcript
NM_007194.4
Coding (HGVS c.)
NM_007194.4:c.1604G>A
Protein (HGVS p.)
NP_009125.1:p.(Arg535His)
GRCh38
chr22:28687925 C>T
GRCh37
chr22:29083913 C>T
ClinVar
128067

Gene diagram

Every interpreted variant in CHEK2, mapped onto the exon structure of NM_007194.4. Select a row to find it on the plot.

CHEK2NM_007194.4
Fetching transcript structure from UCSC…
gnomAD v4.1 146 / 1,594,044 alleles AF 9.16e-05 · 2 homozygotes · FAF 0.00112
gnomAD v2.1 63 / 264,906 alleles AF 0.000238 · 1 homozygotes · FAF 0.00161
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 9.2e-05 · 146 / 1,594,044 alleles · 2 hom · FAF 0.0011
South Asian119 / 90,844 0.00132 hom
Remaining individuals18 / 62,108 0.00029
Admixed American2 / 59,840 3.3e-05
African/African American2 / 74,554 2.7e-05
European (non-Finnish)5 / 1,178,590 4.2e-06
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00024 · 63 / 264,906 alleles · 1 hom · FAF 0.0016
South Asian61 / 30,328 0.0021 hom
Remaining individuals1 / 7,038 0.00014
African/African American1 / 23,358 4.3e-05
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish).

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 9.15909e-05; MAF= 0.00916%, 146/1594044 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00130994; MAF= 0.13099%, 119/90844 alleles, homozygotes = 2); grpmax FAF= 0.00111869.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00023782; MAF= 0.02378%, 63/264906 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00201134; MAF= 0.20113%, 61/30328 alleles, homozygotes = 1); grpmax FAF= 0.00160659.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0004508566275924256, 8/17744 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +61 bp
0.000
SpliceAI acceptor gainat +50 bp
0.000
SpliceAI donor lossat -55 bp
0.000
SpliceAI donor gainat +374 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.020

Other predictors

REVEL
0.046
BayesDel
-0.342

How the predictions were used

BP4 SupportingMultiple independent lines of computational evidence predict no damaging effect: REVEL score 0.046 (below the default 0.5 pathogenicity threshold), BayesDel score -0.342 (negative, strongly supporting benign), SpliceAI max delta 0.00 (no predicted splice alteration), and in silico tools from PMID:30851065 (SIFT: Tolerated, Align GVGD: C0, MutationTaster: Polymorphism). Four independent predictors converge on a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.046 (threshold for pathogenicity is >0.5)
  • BayesDel score -0.342 (negative scores support benign)
  • SpliceAI max delta 0.00 (no splicing impact)
  • SIFT Tolerated
  • Align GVGD C0
  • MutationTaster Polymorphism (0.999)
Sources
PP3 Computational evidence supports a benign interpretation. REVEL score is 0.046 (below the 0.5 threshold for pathogenicity). BayesDel score is -0.342 (negative, supporting benign). SpliceAI max delta is 0.00 (no predicted splice impact). Multiple in silico tools predict no damaging effect. The yeast functional assay (PMID:30851065) also found the variant to be benign. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.046 (benign range)
  • BayesDel score -0.342 (benign range)
  • SpliceAI max delta 0.00 (no splice impact)
  • In silico in PMID:30851065: SIFT Tolerated
  • Align GVGD C0
  • MutationTaster Polymorphism (0.999)
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant (c.1604G>A) is a missense substitution resulting in p.Arg535His. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

In progress — evidence not uploaded yet.

9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures.
    Ow GS et al. · 2014
    No paper-specific finding is recorded.
    PMID 24879340 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.
    Delimitsou A et al. · 2019
    No paper-specific finding is recorded.
    PMID 30851065 ↗
  • Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.
    Fonfria M et al. · 2021
    No paper-specific finding is recorded.
    PMID 34204722 ↗
  • Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants.
    Lim BWX et al. · 2023
    No paper-specific finding is recorded.
    PMID 36315097 ↗
  • ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.
    Stolarova L et al. · 2023
    No paper-specific finding is recorded.
    PMID 37449874 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 9.15909e-05; MAF= 0.00916%, 146/1594044 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00130994; MAF= 0.13099%, 119/90844 alleles, homozygotes = 2); grpmax FAF= 0.00111869.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00023782; MAF= 0.02378%, 63/264906 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00201134; MAF= 0.20113%, 61/30328 alleles, homozygotes = 1); grpmax FAF= 0.00160659.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0004508566275924256, 8/17744 alleles, homozygotes = 0).

ClinVar

In progress — evidence not uploaded yet.

In silico

In progress — evidence not uploaded yet.

Functional

In progress — evidence not uploaded yet.

Somatic

In progress — evidence not uploaded yet.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Literature

In progress — evidence not uploaded yet.