CHEK1c.1070G>AUncertain significance

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Variant interpretation report

CHEK1 c.1070G>A, p.(Ser357Asn)

NM_001274.5:c.1070G>A NP_001265.2:p.(Ser357Asn) 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 CHEK1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 26 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (genomes/exomes), meeting the PM2 threshold of <0.1% population allele frequency.
BP4 (supporting): Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303 (negative/benign), and SpliceAI max delta score 0.03 indicates no significant splice impact. Computational evidence supports a benign interpretation.

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 Not recorded. 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

This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (genomes/exomes), meeting the PM2 threshold of <0.1% population allele frequency.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303 (negative/benign), and SpliceAI max delta score 0.03 indicates no significant splice impact. Computational evidence supports a benign interpretation.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

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. CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies.

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 Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

This missense variant in CHEK1 (c.1070G>A, p.Ser357Asn) is absent from gnomAD population databases (PM2_Supporting).

Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303, and SpliceAI max delta 0.03 indicates no splice impact (BP4_Supporting).

The variant is absent from ClinVar and COSMIC; no experimental functional data, segregation data, or de novo reports were identified.

One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met; these cancel and no pathogenic or benign combination is reached per the generic ACMG/AMP 2015 classification framework. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (genomes/exomes), meeting the PM2 threshold of <0.1% population allele frequency. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes).
Absent from gnomAD v4.1 (genomes/exomes).
Absent from gnomAD-Canada v1.0 (genomes).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303 (negative/benign), and SpliceAI max delta score 0.03 indicates no significant splice impact. Computational evidence supports a benign interpretation. Details ▾Hide ▴

Evidence considered

REVEL: 0.167 (benign-leaning).
BayesDel: -0.303 (benign).
SpliceAI: max delta 0.03 (no predicted splice impact).

Sources

revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 No pathogenic variant with the same amino acid change (p.Ser357Asn) has been reported in ClinVar. This variant is entirely absent from ClinVar. Details ▾Hide ▴

Evidence considered

This variant is absent from ClinVar
no same-amino-acid pathogenic comparator exists.

Sources

clinvar ↗

PS2 No de novo report with confirmed paternity and maternity was identified for this variant. Details ▾Hide ▴

Evidence considered

No de novo data available in evidence sources or literature.

Still missing

No parental testing data available.

PS3 No variant-specific functional data identified. OncoKB reports Unknown Oncogenic Effect. No published experimental studies test c.1070G>A or a systematically characterized range that includes residue S357. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect. No functional studies test this variant. Five PVS1-context papers reviewed
none contain variant-specific functional data.

Still missing

No functional characterization of p.Ser357Asn available.

Sources

oncokb ↗

PS4 No case-control studies, odds ratio data, or statistical enrichment evidence available for this variant. Details ▾Hide ▴

Evidence considered

No case-control or statistical enrichment data available.

Still missing

No case-control data.

PM1 Residue S357 lies in the C-terminal regulatory domain of CHEK1, outside the well-characterized kinase domain (residues ~1-265). Cancerhotspots.org does not identify this position as a statistically significant hotspot. No literature evidence defines S357 as a critical functional domain residue. Details ▾Hide ▴

Evidence considered

Cancerhotspots.org: not a significant hotspot. S357 is in the C-terminal regulatory domain
not the kinase domain. No literature characterizing S357 as a critical functional residue.

PM6 No de novo report was identified for this variant. No confirmed de novo occurrence with parental testing data available. Details ▾Hide ▴

Evidence considered

No de novo data available.

Still missing

No parental testing data.

PP1 No segregation data available for this variant. Cosegregation with disease in affected family members cannot be assessed. Details ▾Hide ▴

Evidence considered

No segregation data available.

Still missing

No family segregation data.

PP2 No HCI prior score or gene-specific missense constraint data available for CHEK1. Low rate of benign missense variation cannot be established without these data. Details ▾Hide ▴

Evidence considered

HCI prior: gene not supported. No missense constraint data available for CHEK1.

Still missing

No CHEK1-specific missense constraint metrics.

PP3 Multiple in silico tools predict a benign effect: REVEL score 0.167 (well below pathogenic threshold of 0.5), BayesDel score -0.303 (negative/benign), SpliceAI max delta 0.03 (no predicted splice impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.167 (benign-leaning).
BayesDel: -0.303 (benign).
SpliceAI: max delta 0.03 (no splicing impact).

Sources

revelbayesdelspliceai ↗

PP4 No patient phenotype data provided to assess specificity for CHEK1-related hereditary cancer predisposition. Details ▾Hide ▴

Evidence considered

No patient phenotype information available.

Still missing

Patient phenotype data not provided.

PP5 Variant is absent from ClinVar; no reputable source has classified this variant. No expert panel classification exists to support pathogenicity. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
no reputable source classification available.

Sources

clinvar ↗

BA1 Variant is absent from gnomAD; does not meet the BA1 threshold of >1% allele frequency in any population. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1
allele frequency is 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Variant is absent from gnomAD; does not meet the BS1 threshold of >0.3% allele frequency in population databases. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1
allele frequency is 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 Variant is absent from population databases; no evidence of observation in healthy adults to support BS2. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD
no observations in healthy adult controls.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No functional studies demonstrating a neutral or benign effect for this variant. In silico scores (REVEL 0.167, BayesDel -0.303) are weakly benign but do not constitute functional data sufficient for BS3. Details ▾Hide ▴

Evidence considered

REVEL 0.167
BayesDel -0.303 indicate benign prediction but are not functional assay data.
No experimental functional studies testing this variant identified.

Still missing

No direct functional data demonstrating a neutral effect.

Sources

revelbayesdel

BS4 No segregation data showing lack of cosegregation with disease. No family-based evidence available to support BS4. Details ▾Hide ▴

Evidence considered

No segregation data available.

Still missing

No family segregation data.

BP1 BP1 applies to truncating variants in genes where only truncating variants cause disease. This is a missense variant, and CHEK1 missense variants have been reported in the germline literature as potentially pathogenic, so BP1 does not apply. Details ▾Hide ▴

Evidence considered

Missense variant in a gene where missense changes have been associated with hereditary cancer predisposition.

BP2 No observation of this variant in trans with a known pathogenic CHEK1 variant. Variant is absent from population databases, precluding assessment of phase with other variants. Details ▾Hide ▴

Evidence considered

No observation in trans with a pathogenic variant. Variant not present in population databases to assess phasing.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP5 No case-level data showing an alternate molecular basis for disease in an individual harboring this variant. Details ▾Hide ▴

Evidence considered

No alternate molecular diagnosis data available.

BP6 Variant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
no benign classification from any source.

Sources

clinvar ↗

PS5 Variant is absent from ClinVar; no expert panel or reputable source has classified this variant as pathogenic. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
no classification exists.

Sources

clinvar ↗

Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense variant (c.1070G>A, p.Ser357Asn) does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴

Evidence considered

Variant is a missense substitution
PVS1 framework requires null variant type.

Sources

pvs1_generic_framework ↗pvs1_variant_assessment

PM5 N/ANo pathogenic missense comparator at the same residue (S357) identified in ClinVar. PM5 candidate search returned no candidates. Details ▾Hide ▴

Evidence considered

PM5 candidate search: no same-residue pathogenic comparators.

Sources

pm5_candidatesclinvar ↗

BP7 N/AThis is a missense variant (c.1070G>A, p.Ser357Asn), not a synonymous variant. BP7 is reserved for synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 applies only to synonymous variants.

Identifiers

Gene: CHEK1
Transcript: NM_001274.5
Coding (HGVS c.): NM_001274.5:c.1070G>A
Protein (HGVS p.): NP_001265.2:p.(Ser357Asn)
GRCh38: chr11:125644237 G>A
GRCh37: chr11:125514132 G>A

Gene diagram

Every interpreted variant in CHEK1, mapped onto the exon structure of NM_001274.5. Select a row to find it on the plot.

CHEK1NM_001274.5

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 CHEK1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +1 bp

0.000

SpliceAI acceptor gainat -141 bp

0.030

SpliceAI donor lossat -100 bp

0.000

SpliceAI donor gainat +31 bp

0.020

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.050

Other predictors

REVEL: 0.167
BayesDel: -0.303

How the predictions were used

Evidence considered

REVEL: 0.167 (benign-leaning).
BayesDel: -0.303 (benign).
SpliceAI: max delta 0.03 (no predicted splice impact).

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.167 (benign-leaning).
BayesDel: -0.303 (benign).
SpliceAI: max delta 0.03 (no splicing impact).

Sources

revelbayesdelspliceai ↗

BP7 N/AThis is a missense variant (c.1070G>A, p.Ser357Asn), not a synonymous variant. BP7 is reserved for synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense variant
BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.167. BayesDel score = -0.303191.

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 Captured gnomAD v4.1 source record Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗

ClinVar Captured ClinVar source record 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 ↗

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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.167. BayesDel score = -0.303191.

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.