CHEK2c.731A>GUncertain significance

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Variant interpretation report

CHEK2 c.731A>G, p.(Lys244Arg)

NM_007194.4:c.731A>G NP_009125.1:p.(Lys244Arg) 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.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen CHEK2 VCEP v1.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): The variant is present at very low frequency in population databases (gnomAD v2.1 AF 1.06e-05, 3/282782; gnomAD v4.1 AF 9.29e-06, 15/1613930) with no homozygotes observed, supporting rarity.
BP4 (supporting): Computational evidence supports a benign effect: REVEL is low at 0.062 and SpliceAI predicts no significant splice impact with max delta score 0.00.

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: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

The variant is present at very low frequency in population databases (gnomAD v2.1 AF 1.06e-05, 3/282782; gnomAD v4.1 AF 9.29e-06, 15/1613930) with no homozygotes observed, supporting rarity.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Computational evidence supports a benign effect: REVEL is low at 0.062 and SpliceAI predicts no significant splice impact with max delta score 0.00.

Recorded classification: Uncertain significance

Generic ACMG/AMP final classification combination rules (fallback used because the CHEK2 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Specification final-classification framework was retrieved but was incomplete and not directly applicable).

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

15 / 1,613,930 alleles

gnomAD v4.1: 15 / 1,613,930 alleles. Recorded AF 9.29408e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.06089e-05; MAF= 0.00106%, 3/282782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00513e-05; MAF= 0.00401%, 1/24968 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only Cancer Hotspots ↗

For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The CHEK2 c.731A>G (p.Lys244Arg) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 7 clinical laboratories.

The variant is present at very low frequency in gnomAD, with AF 1.06e-05 in v2.1 and 9.29e-06 in v4.1, and no homozygotes were observed, which supports rarity.

In silico data argue against a deleterious effect, with REVEL 0.062 and SpliceAI predicting no significant splice impact (max delta score 0.00).

Met · 2

PM2 SupportingThe variant is present at very low frequency in population databases (gnomAD v2.1 AF 1.06e-05, 3/282782; gnomAD v4.1 AF 9.29e-06, 15/1613930) with no homozygotes observed, supporting rarity. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 total AF 1.0608878924401129e-05
gnomAD v4.1 total AF 9.294083386516143e-06
0 homozygotes in both datasets

Still missing

Final strength should be confirmed against any CHEK2-specific PM2 specification if available.

Sources

case_summary.jsonevidence.json

BP4 SupportingComputational evidence supports a benign effect: REVEL is low at 0.062 and SpliceAI predicts no significant splice impact with max delta score 0.00. Details ▾Hide ▴

Evidence considered

REVEL 0.062
SpliceAI DS max 0.00

Still missing

Any CHEK2-specific computational thresholds should be confirmed if later retrieved.

Sources

prefetch.jsonevidence.jsoncase_summary.json

Not met · 4 · evaluated, threshold not reached

PM1 Cancer Hotspots did not identify residue K244 as a statistically significant hotspot, and no mutational hotspot or well-established critical functional residue evidence was retrieved. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: no hotspot row found for CHEK2 K244

Still missing

Domain-specific CHEK2 missense constraint or curated hotspot data would be needed to reconsider this criterion.

Sources

evidence.jsoncase_summary.json

PP3 Available computational evidence does not support a deleterious effect: REVEL is low (0.062) and SpliceAI predicts no significant splice impact (max delta 0.00). Details ▾Hide ▴

Evidence considered

REVEL 0.062
SpliceAI max delta 0.00

Sources

prefetch.jsonevidence.jsoncase_summary.json

BA1 Population frequency is far below stand-alone benign thresholds. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF 9.29e-06

Sources

case_summary.json

BS1 Population frequency is too low to support a benign frequency-based criterion. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF 9.29e-06
gnomAD v2.1 AF 1.06e-05

Sources

case_summary.json

Not assessed · 15 · no assessment recorded

PS1 No evidence was retrieved showing another nucleotide change that produces the same amino acid substitution and is established as pathogenic/likely pathogenic. Details ▾Hide ▴

Still missing

Pathogenic comparator variants encoding p.Lys244Arg were not identified.

PS2 No confirmed de novo data were retrieved. Details ▾Hide ▴

Still missing

Parental testing and phenotype confirmation are unavailable.

PS3 Functional publications were cited in ClinVar/literature triage, but no validated assay result for CHEK2 p.(Lys244Arg) was extracted with sufficient detail to support damaging functional evidence. Details ▾Hide ▴

Evidence considered

PMID:22114986
PMID:37449874

Still missing

Variant-specific functional assay results from PMID:22114986 or PMID:37449874 would need direct review.

Sources

literature_pass.jsoncase_summary.json2211498637449874

PS4 The variant has been reported in ClinVar, but case-control enrichment or a case count meeting ACMG/AMP evidence thresholds was not retrieved. Details ▾Hide ▴

Evidence considered

ClinVar uncertain significance, 7 clinical laboratories

Still missing

Published case counts, control counts, or odds ratio data for this specific variant are needed.

Sources

case_summary.jsonliterature_pass.json221149863347199137449874

PM5 No evidence was retrieved showing a different pathogenic missense change at codon 244. Details ▾Hide ▴

Still missing

Pathogenic missense comparators at Lys244 would be needed.

PM6 No assumed de novo observations were retrieved. Details ▾Hide ▴

Still missing

Parental data are unavailable.

PP1 No segregation data were retrieved. Details ▾Hide ▴

Still missing

Pedigree-level segregation information is needed.

PP2 No gene-level missense constraint or pathogenic missense enrichment evidence specific enough to support PP2 was retrieved. Details ▾Hide ▴

Still missing

CHEK2 missense constraint data or VCEP rule text would be needed.

PP4 No phenotype or family history data were provided to support a highly specific CHEK2-related presentation. Details ▾Hide ▴

Still missing

Clinical phenotype and family history correlation are needed.

BS2 No evidence was retrieved showing the variant in healthy adults at a frequency or context sufficient for BS2. Details ▾Hide ▴

Evidence considered

No homozygotes in gnomAD v2.1 or v4.1

Still missing

Validated unaffected-carrier observations would be needed.

Sources

case_summary.json

BS3 No well-established functional study demonstrating normal CHEK2 protein function for p.(Lys244Arg) was extracted. Details ▾Hide ▴

Evidence considered

PMID:22114986
PMID:37449874

Still missing

Variant-specific benign functional assay results would require direct review of cited publications.

Sources

literature_pass.jsoncase_summary.json2211498637449874

BS4 No segregation data showing lack of cosegregation were retrieved. Details ▾Hide ▴

Still missing

Family segregation data are needed.

BP1 No gene-specific evidence was retrieved to support that truncating variants predominate and that missense variation is generally not disease-causing in CHEK2. Details ▾Hide ▴

Still missing

Gene-level mechanism data or explicit VCEP guidance would be needed.

BP2 No allelic phase or co-occurrence data were retrieved. Details ▾Hide ▴

Still missing

Phase information with another pathogenic variant would be needed.

BP5 No alternate molecular explanation for the phenotype was retrieved. Details ▾Hide ▴

Still missing

Phenotype and full testing context are needed.

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense substitution p.(Lys244Arg) does not represent a predicted loss-of-function variant. Details ▾Hide ▴

Evidence considered

NM_007194.4:c.731A>G
NP_009125.1:p.(Lys244Arg)

Sources

prefetch.jsoncase_summary.json

PM3 N/APM3 is intended for recessive disorders with trans observations and is not applicable to the autosomal dominant CHEK2-related cancer predisposition framework used here. Details ▾Hide ▴

Evidence considered

preferredModeOfInheritance: Autosomal dominant inheritance

Sources

prefetch.json

PM4 N/AThis is a missense substitution rather than a protein length-changing variant. Details ▾Hide ▴

Evidence considered

p.(Lys244Arg) missense

Sources

prefetch.json

PP5 N/APP5 is deprecated and was not used for adjudication. Details ▾Hide ▴

Evidence considered

ClinVar uncertain significance entry noted but PP5 not applied

Sources

case_summary.json

BP3 N/AThis is not an in-frame insertion/deletion in a repetitive region. Details ▾Hide ▴

Evidence considered

single-nucleotide missense substitution

Sources

prefetch.json

BP6 N/ABP6 is deprecated and was not used for adjudication. Details ▾Hide ▴

Evidence considered

ClinVar uncertain significance entry noted but BP6 not applied

Sources

case_summary.json

BP7 N/ABP7 applies to synonymous or certain intronic variants and is not applicable to this missense substitution. Details ▾Hide ▴

Evidence considered

p.(Lys244Arg) missense

Sources

prefetch.json

Identifiers

Gene: CHEK2
Transcript: NM_007194.4
Coding (HGVS c.): NM_007194.4:c.731A>G
Protein (HGVS p.): NP_009125.1:p.(Lys244Arg)
GRCh38: chr22:28711970 T>C
GRCh37: chr22:29107958 T>C

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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in CHEK2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 15 / 1,613,930 alleles AF 9.29e-06 · 0 homozygotes · FAF 7.71e-05

gnomAD v2.1 3 / 282,782 alleles AF 1.06e-05 · 0 homozygotes · FAF 2.92e-06

By genetic ancestry

gnomAD v4.1

AF 9.3e-06 · 15 / 1,613,930 alleles · 0 hom · FAF 7.7e-05

African/African American8 / 74,934	0.00011
Admixed American1 / 60,002	1.7e-05
European (non-Finnish)6 / 1,179,972	5.1e-06

0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, Amish.

gnomAD v2.1

AF 1.1e-05 · 3 / 282,782 alleles · 0 hom · FAF 2.9e-06

African/African American1 / 24,968	4e-05
European (non-Finnish)2 / 129,138	1.5e-05

0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 9.29408e-06; MAF= 0.00093%, 15/1613930 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000106761; MAF= 0.01068%, 8/74934 alleles, homozygotes = 0); grpmax FAF= 7.712e-05.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

BP4 SupportingComputational evidence supports a benign effect: REVEL is low at 0.062 and SpliceAI predicts no significant splice impact with max delta score 0.00. Details ▾Hide ▴

Evidence considered

REVEL 0.062
SpliceAI DS max 0.00

Still missing

Any CHEK2-specific computational thresholds should be confirmed if later retrieved.

Sources

prefetch.jsonevidence.jsoncase_summary.json

PP3 Available computational evidence does not support a deleterious effect: REVEL is low (0.062) and SpliceAI predicts no significant splice impact (max delta 0.00). Details ▾Hide ▴

Evidence considered

REVEL 0.062
SpliceAI max delta 0.00

Sources

prefetch.jsonevidence.jsoncase_summary.json

BP7 N/ABP7 applies to synonymous or certain intronic variants and is not applicable to this missense substitution. Details ▾Hide ▴

Evidence considered

p.(Lys244Arg) missense

Sources

prefetch.json

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 15 / 1,613,930 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record

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

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

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.