CHEK2c.1312G>TUncertain significance

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Variant interpretation report

CHEK2 c.1312G>T, p.(Asp438Tyr)

NM_007194.4:c.1312G>T NP_009125.1:p.(Asp438Tyr) 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

Condition: CHEK2-related cancer predisposition
Inheritance: Autosomal dominant
Evidence used: 1 supporting (benign) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen CHEK2 VCEP v1.0
Other laboratories (ClinVar): 19 Uncertain significance · 12 Likely benign · 1 likely benign
Pipeline record: 7 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PS3 (supporting): The variant p.Asp438Tyr was directly studied in PMID:24390236 (title: 'Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin'). Multiple ClinVar submitters reference functional kinase activity assays for this variant (referenced as Baloch 2014 and Bell 2007), reporting intermediate to reduced kinase activity in some studies but conflicting results across laboratories. Full text of PMID:24390236 and PMID:18571837 were not available in the case folder for independent verification of functional assay details. Supporting strength assigned because the variant was directly studied but functional data are conflicting and no systematic range characterization (tiling/saturation mutagenesis) is documented.
PM1 (moderate): Variant p.Asp438Tyr is located in the serine/threonine kinase domain of CHEK2 (residues ~220-486), a well-established critical functional domain where pathogenic missense variants cluster. The kinase domain is required for CHEK2 checkpoint function, and missense alterations in this domain are a recognized mechanism of CHEK2-related cancer predisposition.
BP4 (supporting): Multiple in silico tools predict a benign effect for this variant. REVEL score is 0.337 (below the pathogenic threshold of 0.5), BayesDel score is -0.013 (predicts benign), and SpliceAI max delta is 0.05 (no predicted splicing impact). These quantitative, variant-specific scores support 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 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: 2 Benign evidence criteria: 1

Pathogenic criteria applied · 2

PS3Supporting

PS3 · supporting

The variant p.Asp438Tyr was directly studied in PMID:24390236 (title: 'Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin'). Multiple ClinVar submitters reference functional kinase activity assays for this variant (referenced as Baloch 2014 and Bell 2007), reporting intermediate to reduced kinase activity in some studies but conflicting results across laboratories. Full text of PMID:24390236 and PMID:18571837 were not available in the case folder for independent verification of functional assay details. Supporting strength assigned because the variant was directly studied but functional data are conflicting and no systematic range characterization (tiling/saturation mutagenesis) is documented.

PM1Moderate

PM1 · moderate

Variant p.Asp438Tyr is located in the serine/threonine kinase domain of CHEK2 (residues ~220-486), a well-established critical functional domain where pathogenic missense variants cluster. The kinase domain is required for CHEK2 checkpoint function, and missense alterations in this domain are a recognized mechanism of CHEK2-related cancer predisposition.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Multiple in silico tools predict a benign effect for this variant. REVEL score is 0.337 (below the pathogenic threshold of 0.5), BayesDel score is -0.013 (predicts benign), and SpliceAI max delta is 0.05 (no predicted splicing impact). These quantitative, variant-specific scores support a benign interpretation.

Recorded classification: Uncertain significance

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CHEK2 Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 supporting, PM1 moderate, BP4 supporting; combination = 1 moderate + 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

606 / 1,613,498 alleles

gnomAD v4.1: 606 / 1,613,498 alleles. Recorded AF 0.000375582. Recorded homozygote count 3.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00038592; MAF= 0.03859%, 109/282442 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00127378; MAF= 0.12738%, 32/25122 alleles, homozygotes = 0); grpmax FAF= 0.00035934.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0005971121485180762, 11/18422 alleles, homozygotes = 0).

No listed criterion applied

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

SpliceAI score

0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

32 reported laboratory submissions

19 Uncertain significance · 12 Likely benign · 1 likely benign. ClinVar API review status: criteria provided, conflicting classifications.

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.

Applied · PS3 → 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, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 7 not met · 8 not assessed · 8 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 variant is located in the kinase domain of CHEK2, a critical functional domain where pathogenic missense variants are known to cluster.

The variant was directly studied in at least one publication (Baloch et al.) examining CHEK2 missense mutations and breast cancer risk, but functional assay results are conflicting across studies — some report reduced kinase activity while others show wild-type-like function.

The variant is present in gnomAD v4.1 at an allele frequency of 0.038% (606 alleles, including 3 homozygotes), which exceeds the PM2 threshold of <0.1% and is notable but below BS1 threshold of >0.3%.

In silico tools do not support a pathogenic role: REVEL score 0.337, BayesDel score -0.013, and SpliceAI max delta 0.05 all indicate a likely benign or indeterminate effect.

ClinVar classification is conflicted between Uncertain significance (19 clinical laboratories) and Likely benign (13 clinical laboratories), with overall review status of criteria provided, single submitter (1-star).

One ClinVar submitter reports non-segregation of this variant with disease in a family and observation in unaffected controls, but the primary literature could not be verified.

Overall, pathogenic evidence (PM1_moderate, PS3_supporting) is balanced by benign evidence (BP4_supporting), resulting in a classification of Uncertain Significance.

Met · 3

PS3 SupportingThe variant p.Asp438Tyr was directly studied in PMID:24390236 (title: 'Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin'). Multiple ClinVar submitters reference functional kinase activity assays for this variant (referenced as Baloch 2014 and Bell 2007), reporting intermediate to reduced kinase activity in some studies but conflicting results across laboratories. Full text of PMID:24390236 and PMID:18571837 were not available in the case folder for independent verification of functional assay details. Supporting strength assigned because the variant was directly studied but functional data are conflicting and no systematic range characterization (tiling/saturation mutagenesis) is documented. Details ▾Hide ▴

Evidence considered

PMID:24390236 title confirms direct study of p.D438Y in CHEK2
ClinVar submitters cite kinase activity assays showing variable results (reduced to WT-like activity).
PMID:18571837 (Bell 2007) cited by ClinVar submitters as secondary functional data source
abstract describes CHEK2 SNP identification and characterization in Ashkenazi Jewish men.

Still missing

Full text of PMID:24390236 and PMID:18571837 not available for independent verification of functional assay methodology and quantitative results.
Conflicting functional data across studies: some report ~70% kinase activity reduction
others report WT-like activity.

Sources

PMID:24390236 ↗PMID:18571837 ↗clinvar ↗

PM1 ModerateVariant p.Asp438Tyr is located in the serine/threonine kinase domain of CHEK2 (residues ~220-486), a well-established critical functional domain where pathogenic missense variants cluster. The kinase domain is required for CHEK2 checkpoint function, and missense alterations in this domain are a recognized mechanism of CHEK2-related cancer predisposition. Details ▾Hide ▴

Evidence considered

Residue 438 is within the CHEK2 kinase catalytic domain.
CHEK2 kinase domain is a recognized functional domain where missense mutations are associated with loss of function and cancer predisposition.

Sources

PMID:24390236 ↗PMID:18571837 ↗

BP4 SupportingMultiple in silico tools predict a benign effect for this variant. REVEL score is 0.337 (below the pathogenic threshold of 0.5), BayesDel score is -0.013 (predicts benign), and SpliceAI max delta is 0.05 (no predicted splicing impact). These quantitative, variant-specific scores support a benign interpretation. Details ▾Hide ▴

Evidence considered

REVEL score: 0.337 (below 0.5 pathogenic threshold).
BayesDel score: -0.013 (predicts benign).
SpliceAI max delta: 0.05 (no splicing impact).

Sources

revelbayesdelspliceai ↗

Not met · 7 · evaluated, threshold not reached

PM2 This variant is present in gnomAD v4.1 at an allele frequency of 0.03756% (606/1,613,498 alleles, including 3 homozygotes) with grpmax FAF of 0.23% in the Amish population. This exceeds the PM2 threshold of <0.1% allele frequency in population databases. gnomAD v2.1 similarly shows AF 0.03859% (109/282,442 alleles). Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF 0.03756% (606/1
613
498 alleles
3 homozygotes)
grpmax FAF 0.232% (Amish).
gnomAD v2.1: AF 0.03859% (109/282
442 alleles
0 homozygotes)
grpmax FAF 0.036% (Finnish).

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 In silico tools do not consistently predict a damaging effect. REVEL score is 0.337 (below the commonly accepted pathogenicity threshold of 0.5), BayesDel score is -0.013 (predicts benign), and SpliceAI max delta is 0.05 (no predicted splicing impact). While one ClinVar submitter reported 4 of 5 in silico tools predicted damaging effect, the quantitative scores available for this adjudication indicate a benign or indeterminate prediction. Details ▾Hide ▴

Evidence considered

REVEL score: 0.337 (below 0.5 pathogenic threshold).
BayesDel score: -0.013 (predicts benign).
SpliceAI max delta: 0.05 (no splicing impact).

Sources

revelbayesdelspliceai ↗

PP5 ClinVar review status is 'criteria provided, single submitter' (1-star). PP5 requires a 3-star expert panel review status or higher. Overall ClinVar classification is conflicting between Uncertain significance (19 submitters) and Likely benign (13 submitters). Details ▾Hide ▴

Evidence considered

ClinVar review status: criteria provided
single submitter (1-star).
Classification is conflicting: 19 VUS vs 13 Likely benign submissions.

Sources

clinvar ↗

BA1 gnomAD v4.1 allele frequency 0.03756% is well below the BA1 threshold of >1%. The highest subpopulation frequency (Amish) is 0.55%, which also falls below the 1% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 overall AF: 0.03756%.
Highest subpopulation (Amish) AF: 0.55%.
BA1 threshold: >1%.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 gnomAD v4.1 allele frequency 0.03756% and gnomAD v2.1 AF 0.03859% are both below the BS1 threshold of >0.3%. The grpmax FAF of 0.23% in v4.1 (Amish) also falls below the 0.3% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 overall AF: 0.03756%
grpmax FAF: 0.232%.
gnomAD v2.1 overall AF: 0.03859%
grpmax FAF: 0.036%.
BS1 threshold: >0.3%.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 Observed in 3 homozygous individuals in gnomAD v4.1. However, CHEK2-related cancer predisposition has incomplete penetrance and adult onset; BS2 requires observation in healthy adults for a disorder with full penetrance expected at an early age. The presence of homozygotes is notable but does not satisfy the strict BS2 criteria given the moderate-penetrance, adult-onset nature of CHEK2-associated cancer risk. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 3 homozygous individuals observed.
CHEK2 cancer predisposition is autosomal dominant with incomplete penetrance and adult onset
not meeting BS2 requirement for full penetrance at early age.

Sources

gnomad_v4 ↗

BP6 ClinVar review status is 'criteria provided, single submitter' (1-star). BP6 requires a 3-star expert panel review or higher with a benign or likely benign classification. The overall ClinVar classification is conflicted between VUS and Likely benign. Details ▾Hide ▴

Evidence considered

ClinVar review status: criteria provided
single submitter (1-star).
Classification is conflicting: 19 VUS vs 13 Likely benign submissions.

Sources

clinvar ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo data available for this variant. Details ▾Hide ▴

Still missing

No de novo testing or trio data available in case materials.

PS4 Multiple cohort studies are referenced in ClinVar submissions (PMIDs: 25186627, 27443514, 29484706, 29987844, 36260514, 37656691) but variant-specific case-control or enrichment data could not be independently verified from available abstracts. The ClinVar LabCorp submission additionally notes the variant was observed in unaffected controls. Details ▾Hide ▴

Evidence considered

Literature triage identified PS4 candidate papers but abstracts and available full texts lack variant-specific quantitative case-control data.

Still missing

Full texts of PS4 candidate papers not available for variant-specific enrichment analysis.
ClinVar LabCorp submission reports observation in controls suggesting no strong enrichment.

PM6 No de novo data available for this variant. Details ▾Hide ▴

Still missing

No de novo testing or trio data available in case materials.

PP1 Segregation data referenced in ClinVar submissions: the LabCorp submission (SCV000698770) reports that this variant did not segregate with disease in at least one family and was also observed in unaffected controls. However, the primary literature supporting these claims (referenced as 'baloch_2') is not available for independent verification. Details ▾Hide ▴

Evidence considered

ClinVar LabCorp submission reports non-segregation in one family
primary source unavailable for verification.

Still missing

Primary literature for segregation analysis not available to confirm non-segregation claim.

Sources

clinvar ↗

PP4 Variant reported in individuals with personal or family history of breast, prostate, or colorectal cancer per ClinVar submissions, but also reported in unaffected controls. Specific patient phenotypes could not be independently verified from available primary literature. Details ▾Hide ▴

Evidence considered

ClinVar submissions note observation in cancer-affected individuals but also in controls
no verified patient-level phenotype data available.

Still missing

Patient phenotype data not available for independent verification.
Observed in both affected and unaffected individuals per ClinVar reports.

Sources

clinvar ↗

BS3 Functional studies referenced by ClinVar submitters are conflicting: some studies report reduced kinase activity (~70% decrease per one submitter), while others, including a human cell-based assay, show activity comparable to wild-type. Full texts of the primary functional studies (PMID:24390236, PMID:18571837) were not available for independent assessment of assay methodology and results. Details ▾Hide ▴

Evidence considered

ClinVar GeneDx submission: functional studies 'inconclusive/conflicting' with some showing WT-like activity.
ClinVar Sinai submission: ~70% kinase activity decrease reported but acknowledges conflicting data.

Still missing

Full texts of functional studies not available to resolve conflicting functional data.
Need independent assessment of which assays used physiological conditions vs overexpression systems.

Sources

clinvar ↗

BS4 One ClinVar submitter (LabCorp, SCV000698770, classified Likely benign) reports that this variant did not segregate with disease in at least one family and was also observed in unaffected controls. The primary literature supporting this claim is referenced as 'baloch_2' (likely a study of the Balochistan population) but the full text is not available for independent verification of the segregation analysis. Details ▾Hide ▴

Evidence considered

ClinVar LabCorp submission reports non-segregation in one family
primary source unavailable for verification.

Still missing

Primary literature for segregation analysis unavailable.
Cannot independently verify the number of affected family members or statistical significance of non-segregation.

Sources

clinvar ↗

BP5 No observation of this variant in an individual with an alternate molecular basis for disease. BP5 requires a case where another pathogenic variant explains the phenotype. Details ▾Hide ▴

Still missing

No alternate molecular basis data available.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense variant (c.1312G>T, p.Asp438Tyr); does not meet PVS1 null-variant criteria of nonsense, frameshift, or canonical splice ±1,2 consensus variants. Details ▾Hide ▴

Evidence considered

Variant type is missense substitution
PVS1 decision tree assigns null-variant buckets only to nonsense
frameshift
or canonical splice variants.

Sources

pvs1_generic_framework ↗

PS1 N/ANo different nucleotide change at the same amino acid position with established pathogenicity is known. Details ▾Hide ▴

Evidence considered

No same-residue pathogenic comparator with a different nucleotide change identified in ClinVar or literature.

PM5 N/ANo same-residue pathogenic comparator variants with a different amino acid change were identified. Details ▾Hide ▴

Evidence considered

PM5 candidate search returned no eligible comparators at residue 438.

PP2 N/ACHEK2 is not a gene where missense variants are the predominant pathogenic mechanism; both truncating and missense variants are established as disease-associated. PP2 applies only when missense is the primary mechanism and benign missense variation is rare. Details ▾Hide ▴

Evidence considered

CHEK2 has well-characterized pathogenic truncating variants (e.g.
c.1100delC) in addition to pathogenic missense variants.

BP1 N/ABP1 applies when a missense variant occurs in a gene where truncating variants are the only known pathogenic mechanism. In CHEK2, both truncating (e.g., c.1100delC) and missense variants are established as pathogenic, so BP1 does not apply. Details ▾Hide ▴

Evidence considered

CHEK2 has well-characterized pathogenic missense variants in addition to truncating variants
BP1 is not applicable.

BP2 N/ANo observation of this variant in trans with a known pathogenic CHEK2 variant. Without such observation, BP2 cannot be applied. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous variants with no predicted splicing impact. This is a missense variant (c.1312G>T, p.Asp438Tyr). Details ▾Hide ▴

Evidence considered

Variant is missense
BP7 only applies to synonymous variants.

PS5 N/ANo de novo observation reported for this variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: CHEK2
Transcript: NM_007194.4
Coding (HGVS c.): NM_007194.4:c.1312G>T
Protein (HGVS p.): NP_009125.1:p.(Asp438Tyr)
GRCh38: chr22:28695190 C>A
GRCh37: chr22:29091178 C>A
ClinVar: 376746, 128056

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 v4.1 606 / 1,613,498 alleles AF 0.000376 · 3 homozygotes · FAF 0.00232

gnomAD v2.1 109 / 282,442 alleles AF 0.000386 · 0 homozygotes · FAF 0.000359

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00038 · 606 / 1,613,498 alleles · 3 hom · FAF 0.0023

Amish5 / 910	0.0055
Middle Eastern21 / 6,054	0.0035
European (Finnish)78 / 64,006	0.0012
South Asian37 / 91,060	0.000412 hom
European (non-Finnish)437 / 1,179,526	0.000371 hom
Remaining individuals17 / 62,476	0.00027
Admixed American6 / 59,992	0.0001
African/African American5 / 75,008	6.7e-05

0 alternate alleles recorded in 2 other groups: East Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00039 · 109 / 282,442 alleles · 0 hom · FAF 0.00036

European (Finnish)32 / 25,122	0.0013
European (non-Finnish)60 / 128,792	0.00047
Remaining individuals3 / 7,208	0.00042
South Asian9 / 30,610	0.00029
African/African American3 / 24,960	0.00012
Admixed American2 / 35,428	5.6e-05

0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, East Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000375582; MAF= 0.03756%, 606/1613498 alleles, homozygotes = 3) and has highest observed frequency in the Amish population (AF= 0.00549451; MAF= 0.54945%, 5/910 alleles, homozygotes = 0); grpmax FAF= 0.00232412.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0005971121485180762, 11/18422 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +19 bp

0.050

SpliceAI acceptor gainat +46 bp

0.020

SpliceAI donor lossat -63 bp

0.020

SpliceAI donor gainat -93 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: 0.337
BayesDel: -0.014

How the predictions were used

Evidence considered

REVEL score: 0.337 (below 0.5 pathogenic threshold).
BayesDel score: -0.013 (predicts benign).
SpliceAI max delta: 0.05 (no splicing impact).

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL score: 0.337 (below 0.5 pathogenic threshold).
BayesDel score: -0.013 (predicts benign).
SpliceAI max delta: 0.05 (no splicing impact).

Sources

revelbayesdelspliceai ↗

BP7 N/ABP7 applies only to synonymous variants with no predicted splicing impact. This is a missense variant (c.1312G>T, p.Asp438Tyr). Details ▾Hide ▴

Evidence considered

Variant is missense
BP7 only applies to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.337. BayesDel score = -0.0136704.

8 paper records listed. 2 cited in the classification.

Cited in the classification

Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer.

Sequenced CHEK2 in 75 Ashkenazi Jewish individuals (25 prostate cancer, 25 breast cancer, 25 controls) and identified seven coding SNPs (five novel). The abstract does not specify whether NM_007194.4:c.1312G>T (p.D438Y) was among the identified SNPs. ClinVar submitters reference this study (as Bell 2007) as a source of functional kinase assay data for this variant.
→ PS3 → PM1 Does not name this variant
PMID 18571837 ↗
Source detail

We identified seven coding SNPs (five are novel) that changed the amino-acid sequence.

Location Abstract only; full text not available in case folder
Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin.

Directly studied CHEK2 p.D438Y (NM_007194.4:c.1312G>T) missense variant in women of Balochistan origin and reported association with breast cancer risk. ClinVar submitters cite this study as containing functional kinase activity data for this variant, with reported variable results across assays.
→ PS3 → PM1 Names this variant
PMID 24390236 ↗
Source detail

Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin.

Location Title and abstract; full text not available in case folder

Other recorded publications

DNA repair genes are selectively mutated in diffuse large B cell lymphomas.

Examined DNA repair gene mutations in diffuse large B cell lymphomas by targeted sequencing of 73 DNA repair genes in 29 B cell lymphoma samples. This is a somatic/tumor study, not a germline variant study. NM_007194.4:c.1312G>T was not identified in the abstract.
Does not name this variant
PMID 23960188 ↗
Targeted genomic analysis of Müllerian adenosarcoma.

Howitt BE et al. · 2015

Targeted genomic analysis of Müllerian adenosarcoma, a rare gynecologic tumor. This is a somatic tumor study with gene-level CHEK2 findings. NM_007194.4:c.1312G>T (p.Asp438Tyr) was not identified in the abstract.
Does not name this variant
PMID 25231023 ↗
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.

ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological guideline paper that does not discuss individual CHEK2 variants. NM_007194.4:c.1312G>T was not identified in this paper.
Does not name this variant
PMID 25741868 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Describes a standardized DNA variant scoring system for pathogenicity assessments in Mendelian disorders. This is a methodological paper that does not discuss individual CHEK2 variants. NM_007194.4:c.1312G>T was not identified in this paper.
Does not name this variant
PMID 26467025 ↗
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.

Studied rare protein-truncating variants in ATM, CHEK2, and PALB2 in 13,087 breast cancer cases and 5,488 controls. Focused exclusively on truncating variants; this paper does not discuss CHEK2 missense variants including NM_007194.4:c.1312G>T (p.Asp438Tyr).
Does not name this variant
PMID 28779002 ↗
A novel founder CHEK2 mutation is associated with increased prostate cancer risk.

Cybulski C et al. · 2004

Investigated CHEK2 founder mutations (IVS2+1G>A and 1100delC) in Polish prostate cancer patients. This paper studied truncating CHEK2 mutations, not missense variants. NM_007194.4:c.1312G>T (p.Asp438Tyr) was not identified in the abstract or title.
Does not name this variant
PMID 15087378 ↗

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

gnomAD v4.1 606 / 1,613,498 recorded alleles Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.050 Open source ↗

ClinVar 19 Uncertain significance · 12 Likely benign · 1 likely benign 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

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0005971121485180762, 11/18422 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (19 clinical laboratories) and as Likely benign (12 clinical laboratories) and as likely benign (1 clinical laboratory). (ClinVarID = 128056)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.337. BayesDel score = -0.0136704.

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.