0%
CHEK2c.1392G>TUncertain significance
Print report
Variant interpretation report

CHEK2 c.1392G>T, p.(Lys464Asn)

NM_007194.4:c.1392G>T NP_009125.1:p.(Lys464Asn) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

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 v1.0.0. 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: 2 Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting

The variant is located in the CHEK2 kinase domain (residues 220-486), a well-established critical functional domain where numerous pathogenic missense variants cluster. p.Lys464Asn falls within the kinase domain activation segment, supporting a role in protein function disruption.

PM2Supporting
PM2 · supporting

The variant is extremely rare in population databases. gnomAD v2.1 reports 1 allele in 233,756 (AF=4.28e-6, 0.00043%), and gnomAD v4.1 reports 0 alleles in 1,594,506. This is well below the PM2 threshold of <0.1% (0.001) for a rare variant absent or at extremely low frequency in controls.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel is -0.221 (benign-leaning), and SpliceAI max delta is 0.27 (below the splice-impact threshold of 0.5). HCI prior is not available for CHEK2. Together, these suggest the missense change is not predicted to be damaging.

Recorded classification: Uncertain significance

Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, which maps to VUS.

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
0 / 1,594,506 alleles

gnomAD v4.1: 0 / 1,594,506 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.27797e-06; MAF= 0.00043%, 1/233756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19676e-06; MAF= 0.00092%, 1/108734 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.270 maximum delta

Recorded SpliceAI maximum delta score: 0.270. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

5 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.

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.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen CHEK2 VCEP v1.0.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 17 not met · 4 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_007194.4:c.1392G>T (p.Lys464Asn) is a missense variant in CHEK2 located in the kinase domain where pathogenic missense variants cluster.

This variant is extremely rare in population databases, with 1 allele in 233,756 in gnomAD v2.1 (AF=4.28e-6) and 0 alleles in 1,594,506 in gnomAD v4.1.

Multiple lines of computational evidence (REVEL=0.321, BayesDel=-0.221, SpliceAI max delta=0.27) suggest no significant impact on the gene product.

This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (VariationID 530112) with no pathogenic assertion from any reputable source.

PVS1 is not applicable as this is a missense change. No de novo, segregation, case-control, same-residue comparator, or confirmed functional evidence was available from verified sources to support pathogenicity.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PM1 (supporting) + PM2 (supporting) + BP4 (supporting benign) results in insufficient evidence to classify as pathogenic, likely pathogenic, or likely benign. The variant remains a Variant of Uncertain Significance (VUS).

Met · 3

PM1 SupportingThe variant is located in the CHEK2 kinase domain (residues 220-486), a well-established critical functional domain where numerous pathogenic missense variants cluster. p.Lys464Asn falls within the kinase domain activation segment, supporting a role in protein function disruption. Details ▾Hide ▴
Evidence considered
  • CHEK2 kinase domain spans residues 220-486 (UniProt O96017)
  • K464 is within the kinase domain where pathogenic missense variants are enriched.
  • VCEP specification v1.0.0 defines CHEK2 as a cancer predisposition gene with disease mechanism involving both truncating and missense variants.
Still missing
  • No CHEK2 VCEP-specific PM1 domain/hotspot boundaries formally defined in the retrieved criteria.
Sources
cspec ↗
PM2 SupportingThe variant is extremely rare in population databases. gnomAD v2.1 reports 1 allele in 233,756 (AF=4.28e-6, 0.00043%), and gnomAD v4.1 reports 0 alleles in 1,594,506. This is well below the PM2 threshold of <0.1% (0.001) for a rare variant absent or at extremely low frequency in controls. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1/233
  • 756 alleles (AF=4.28e-6
  • 0 homozygotes).
  • gnomAD v4.1: 0/1
  • 594
  • 506 alleles (AF=0
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel is -0.221 (benign-leaning), and SpliceAI max delta is 0.27 (below the splice-impact threshold of 0.5). HCI prior is not available for CHEK2. Together, these suggest the missense change is not predicted to be damaging. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.321 (<0.5).
  • BayesDel: -0.221 (negative score
  • benign-leaning).
  • SpliceAI max delta: 0.27 (<0.5).
Sources
revelbayesdelspliceai ↗

Not met · 17 · evaluated, threshold not reached

PS1 No alternative nucleotide change resulting in the same amino acid substitution (p.Lys464Asn) has been reported as pathogenic. PS1 requires a different nucleotide variant producing the same missense change to have been established as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 530112 records only NM_007194.4:c.1392G>T at this residue
  • PM5 candidate harvest found no same-residue comparator variants.
Still missing
  • No alternative nucleotide change at codon 464 producing p.Lys464Asn identified in ClinVar or literature.
Sources
clinvar ↗pm5_candidates
PS2 No confirmed de novo occurrence of NM_007194.4:c.1392G>T has been reported. A systematic search of PubMed and ClinVar for de novo observations yielded no results. Details ▾Hide ▴
Evidence considered
  • No de novo assertion in ClinVar submissions (5 submitters
  • all classify as VUS with no de novo origin reported)
  • exploratory PubMed search identified no de novo report.
Still missing
  • No de novo observation reported in any published study.
Sources
clinvar ↗3744987429522266
PS4 Insufficient case-control data to establish statistically significant enrichment of this variant in affected individuals. Le Calvez-Kelm et al. (PMID:21876083, not in source registry) reported K464N in 1/1308 breast cancer cases and 0/1109 controls. The variant is present in gnomAD v2.1 at extremely low frequency (1/233,756 alleles). These numbers are too small for any statistical comparison meeting PS4 thresholds. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1 allele in 233
  • 756 (AF=4.28e-6)
  • gnomAD v4.1: 0 alleles in 1
  • 594
  • 506.
  • ClinVar: 5 clinical laboratory submissions
  • all uncertain significance.
  • Exploratory search identified 1 case / 0 controls in Le Calvez-Kelm et al. 2011
  • insufficient for PS4.
Still missing
  • No large case-control study with statistically significant odds ratio for K464N.
  • CIMBA consortium data or larger aggregated cohorts may contain additional case counts.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗29522266
PM5 No pathogenic missense variant at the same amino acid residue (Lys464) has been identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants with pathogenic or likely pathogenic classification. Details ▾Hide ▴
Evidence considered
  • Zero same-residue candidates at CHEK2 Lys464
  • PM5 candidate harvest returned empty.
Still missing
  • No known pathogenic missense variant at residue Lys464 to serve as comparator.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence of NM_007194.4:c.1392G>T has been reported, with or without confirmation of parentage. PM6 requires a de novo observation where maternity/paternity has not been confirmed. Details ▾Hide ▴
Evidence considered
  • No de novo assertion in any ClinVar submission
  • no de novo report identified in literature search.
Still missing
  • No de novo observation reported.
Sources
clinvar ↗
PP1 No cosegregation data with disease in multiple affected family members has been reported for this variant. A search of PubMed and ClinVar yielded no family studies tracing NM_007194.4:c.1392G>T with cancer phenotypes. Details ▾Hide ▴
Evidence considered
  • No cosegregation data in ClinVar submissions
  • no family studies published.
Still missing
  • No family studies with multiple affected carriers of c.1392G>T available.
Sources
clinvar ↗
PP3 Multiple lines of in silico evidence do not support a damaging effect. REVEL score is 0.321 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.221 (benign-leaning, below zero), and SpliceAI max delta is 0.27 (below the typical splice-impact threshold of 0.5). HCI prior probability is not available for CHEK2. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.321 (<0.5 pathogenic threshold).
  • BayesDel: -0.221 (benign-leaning).
  • SpliceAI max delta: 0.27 (<0.5 splice-impact threshold).
  • HCI prior: not supported for CHEK2.
Sources
revelbayesdelspliceai ↗
PP5 No reputable source classifies this variant as pathogenic. ClinVar records 5 clinical laboratory submissions all reporting Uncertain significance. No expert panel classification or reputable source asserting pathogenicity was identified. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 530112: 5 submissions
  • all Uncertain significance (criteria provided
  • single submitter).
  • No expert panel or reputable source asserting pathogenic or likely pathogenic.
Sources
clinvar ↗
BA1 The variant allele frequency is far below 1%. gnomAD v2.1 AF is 4.28e-6 (0.00043%), v4.1 AF is 0. BA1 requires an allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 4.28e-6 (0.00043%).
  • gnomAD v4.1 AF: 0.
  • BA1 threshold: >1% (0.01)
  • not approached.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant allele frequency is far below the BS1 threshold of >0.3%. The highest observed subpopulation frequency is 9.20e-6 (0.00092%) in European (non-Finnish) in gnomAD v2.1, and 0 in v4.1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 max subpopulation AF: 9.20e-6 (NFE
  • 0.00092%).
  • gnomAD v4.1 max subpopulation AF: 0.
  • BS1 threshold >0.3% (0.003)
  • not approached.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No evidence that this variant has been observed in healthy adult individuals in the absence of disease for a fully penetrant disorder. BS2 requires observation in multiple healthy individuals without the associated phenotype. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1 carrier out of 233
  • 756
  • phenotype of this individual is unknown (gnomAD excludes severe pediatric disease but does not exclude adult-onset cancer).
  • Insufficient to establish the variant as benign based on population observation.
Still missing
  • No published report of this variant in healthy controls with documented absence of cancer.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Available functional evidence, although not confirmed via full-text verification, suggests a damaging rather than benign effect (see PS3). No well-established functional study demonstrates a benign effect for this variant. Details ▾Hide ▴
Evidence considered
  • Exploratory functional evidence suggests loss of kinase activity (damaging)
  • BS3 requires functional studies showing no damaging effect.
  • No contradictory benign functional data identified.
Still missing
  • Full-text confirmation needed for functional studies to exclude BS3 definitively.
Sources
PMID:37449874 ↗37449874
BS4 No evidence demonstrating lack of cosegregation with disease in affected families. BS4 requires observation of the variant in multiple unrelated healthy individuals from families with the disease, demonstrating non-segregation. Details ▾Hide ▴
Evidence considered
  • No published family study demonstrating non-segregation of c.1392G>T with CHEK2-related cancers.
Still missing
  • No segregation data available to evaluate BS4.
BP1 BP1 is applicable when a missense variant occurs in a gene where primarily truncating variants cause disease. CHEK2-related cancer predisposition involves both truncating and missense pathogenic variants; the kinase domain is a well-established location for pathogenic missense changes. Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • CHEK2 disease mechanism includes both missense and truncating pathogenic variants
  • the kinase domain (where K464 is located) is a known cluster for pathogenic missense variants.
Sources
cspec ↗
BP2 No observation of this variant in trans with a known pathogenic CHEK2 variant in a healthy individual has been reported. gnomAD shows no homozygotes, and no phase information is available for compound heterozygous assessment. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0 homozygotes
  • gnomAD v4.1: 0 homozygotes.
  • No published report of this variant in trans with a pathogenic CHEK2 variant.
Still missing
  • No phase-resolved data available to assess trans configuration with pathogenic variants.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP6 No reputable source classifies this variant as benign or likely benign. ClinVar records 5 clinical laboratory submissions, all reporting Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 530112: all 5 submissions classify as Uncertain significance
  • no benign or likely benign assertion from any source.
Sources
clinvar ↗
PS5 PS5 requires a different pathogenic missense variant at the same amino acid residue with additional supporting evidence. No pathogenic missense variant at CHEK2 residue Lys464 was identified in ClinVar or the PM5 candidate harvest. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvest found zero same-residue candidates at Lys464
  • no pathogenic or likely pathogenic missense at this position identified in ClinVar.
Still missing
  • No pathogenic missense variant at Lys464 identified as comparator.
Sources
pm5_candidatesclinvar ↗

Not assessed · 4 · no assessment recorded

PS3 Exploratory literature search identified functional studies (Delia et al. 2004, PMID:15239148; Roeb et al. 2012, PMID:22419737) reporting loss of kinase activity for p.Lys464Asn, suggesting a damaging effect. However, these PMIDs are not present in the case source registry and no full-text was retrieved for confirmation. PS3 cannot be applied without verified functional evidence from a reviewed full-text source. Details ▾Hide ▴
Evidence considered
  • ENIGMA CHEK2gether project (PMID:37449874) functionally characterized 460 CHEK2 missense VUS
  • specific variant K464N status within this study could not be confirmed from abstract alone.
  • Exploratory pass identified Delia et al. 2004 (PMID:15239148) and Roeb et al. 2012 (PMID:22419737) reporting damaging functional impact for K464N
  • but these were not retrieved as full-text.
Still missing
  • Full-text verification needed for PMID:37449874 (ENIGMA CHEK2gether) to confirm whether K464N was among the functionally characterized variants.
  • PMID:15239148 (Delia et al. 2004) and PMID:22419737 (Roeb et al. 2012) were identified by exploratory search but not retrieved as full-text.
Sources
PMID:37449874 ↗37449874
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. CHEK2 has both truncating and missense pathogenic variants, but also a substantial number of missense VUS. Without explicit VCEP guidance defining CHEK2 as meeting PP2 criteria, this criterion cannot be reliably applied. Details ▾Hide ▴
Evidence considered
  • CHEK2 VCEP specification v1.0.0 does not provide explicit PP2 criteria or thresholds for rate of benign missense variation.
  • CHEK2 disease mechanism involves both truncating and missense pathogenic variants.
Still missing
  • No VCEP-defined PP2 applicability for CHEK2 missense variants.
  • Quantitative rate of benign missense variation in CHEK2 not established in the retrieved evidence.
Sources
cspec ↗
PP4 No patient-specific phenotypic information or family history was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
  • No proband phenotype
  • family history
  • or clinical indication provided in the case materials.
Still missing
  • Patient phenotype and family history not available for assessment.
BP5 Insufficient data to determine whether this variant has been observed in a case with an alternate molecular basis for disease. No information about co-occurring pathogenic variants in other genes was available in the case materials. Details ▾Hide ▴
Evidence considered
  • No data on alternate molecular diagnoses in carriers of this variant.
Still missing
  • No information on co-occurring pathogenic variants in other cancer predisposition genes.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_007194.4:c.1392G>T is a missense substitution (p.Lys464Asn) and does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution (c.1392G>T
  • p.Lys464Asn)
  • ClinGen SVI PVS1 decision tree (PMC6185798) restricts PVS1 to null variants predicted to undergo NMD.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CHEK2-related cancer predisposition is an autosomal dominant disorder; biallelic CHEK2 variants cause Fanconi anemia type J, a distinct recessive condition, but PM3 was designated as trivially not_applicable for this adjudication. Details ▾Hide ▴
Evidence considered
  • Designated as trivially not_applicable per adjudication instructions.
PM4 N/APM4 applies to non-frameshift insertions/deletions or stop-loss variants. NM_007194.4:c.1392G>T is a single-nucleotide missense substitution, not an indel or stop-loss. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not an indel or stop-loss.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. NM_007194.4:c.1392G>T is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
  • Variant is a substitution
  • not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_007194.4:c.1392G>T is a missense substitution (p.Lys464Asn), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Identifiers

Gene
CHEK2
Transcript
NM_007194.4
Coding (HGVS c.)
NM_007194.4:c.1392G>T
Protein (HGVS p.)
NP_009125.1:p.(Lys464Asn)
GRCh38
chr22:28694101 C>A
GRCh37
chr22:29090089 C>A
ClinVar
530112

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 0 / 1,594,506 alleles AF 0 · 0 homozygotes
gnomAD v2.1 1 / 233,756 alleles AF 4.28e-06 · 0 homozygotes
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,594,506 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

gnomAD v2.1

AF 4.3e-06 · 1 / 233,756 alleles · 0 hom
European (non-Finnish)1 / 108,734 9.2e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1594506 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74920 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.27797e-06; MAF= 0.00043%, 1/233756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19676e-06; MAF= 0.00092%, 1/108734 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +16 bp
0.270
SpliceAI acceptor gainat -14 bp
0.000
SpliceAI donor lossat -69 bp
0.200
SpliceAI donor gainat +16 bp
0.000
Pangolin splice lossmagnitude shown
-0.180
Pangolin splice gain
0.010

Other predictors

REVEL
0.321
BayesDel
-0.221

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel is -0.221 (benign-leaning), and SpliceAI max delta is 0.27 (below the splice-impact threshold of 0.5). HCI prior is not available for CHEK2. Together, these suggest the missense change is not predicted to be damaging. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.321 (<0.5).
  • BayesDel: -0.221 (negative score
  • benign-leaning).
  • SpliceAI max delta: 0.27 (<0.5).
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of in silico evidence do not support a damaging effect. REVEL score is 0.321 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.221 (benign-leaning, below zero), and SpliceAI max delta is 0.27 (below the typical splice-impact threshold of 0.5). HCI prior probability is not available for CHEK2. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.321 (<0.5 pathogenic threshold).
  • BayesDel: -0.221 (benign-leaning).
  • SpliceAI max delta: 0.27 (<0.5 splice-impact threshold).
  • HCI prior: not supported for CHEK2.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_007194.4:c.1392G>T is a missense substitution (p.Lys464Asn), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.321. BayesDel score = -0.220536.

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

  • 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 ↗
  • Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
    No paper-specific finding is recorded.
    PMID 34242744 ↗
  • 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.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    No paper-specific finding is recorded.
    PMID 17508274 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301425 ↗
  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    Moyer VA et al. · 2014
    No paper-specific finding is recorded.
    PMID 24366376 ↗
  • 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.

gnomAD v4.1 0 / 1,594,506 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.270 Open source ↗
ClinVar 5 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

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= 0; MAF= 0.00000%, 0/1594506 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74920 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.27797e-06; MAF= 0.00043%, 1/233756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19676e-06; MAF= 0.00092%, 1/108734 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 530112)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.321. BayesDel score = -0.220536.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.