This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 338 of the CHEK2 protein (p.Leu338Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with features of hereditary cancer (PMID: 31159747, 34326862). ClinVar contains an entry for this variant (Variation ID: 142406). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1012C>T (p.Leu338Phe)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1012C>T (p.Leu338Phe)
Variation ID: 142406 Accession: VCV000142406.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28696984 (GRCh38) [ NCBI UCSC ] 22: 29092972 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 16, 2017 May 1, 2024 Nov 16, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.1012C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Leu338Phe missense NM_001005735.2:c.1141C>T NP_001005735.1:p.Leu381Phe missense NM_001257387.2:c.349C>T NP_001244316.1:p.Leu117Phe missense NM_001349956.2:c.811C>T NP_001336885.1:p.Leu271Phe missense NM_145862.2:c.1009-1111C>T intron variant NC_000022.11:g.28696984G>A NC_000022.10:g.29092972G>A NG_008150.2:g.49883C>T LRG_302:g.49883C>T LRG_302t1:c.1012C>T LRG_302p1:p.Leu338Phe - Protein change
- L338F, L117F, L271F, L381F
- Other names
- -
- Canonical SPDI
- NC_000022.11:28696983:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4050 | 4106 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 12, 2023 | RCV000131506.12 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 16, 2023 | RCV000199485.13 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
May 18, 2021 | RCV000487089.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821987.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
|
Uncertain significance
(Dec 16, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537014.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1012C>T (p.L338F) missense variant has been reported in at least one individual undergoing multigene testing for hereditary cancer (PMID: 31159747). This variant was … (more)
The CHEK2 c.1012C>T (p.L338F) missense variant has been reported in at least one individual undergoing multigene testing for hereditary cancer (PMID: 31159747). This variant was not present individuals with breast cancer in a large dataset of 60,466 women with breast cancer but was present in 2/53,461 controls (PMID 33471991). This variant was not observed in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 142406). In silico tools suggest the impact of the variant on protein function is deleterious, though functional studies in yeast indicate that the variant has no impact on growth (PMID 30851065). The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Nov 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254917.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 338 of the CHEK2 protein (p.Leu338Phe). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 338 of the CHEK2 protein (p.Leu338Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with features of hereditary cancer (PMID: 31159747, 34326862). ClinVar contains an entry for this variant (Variation ID: 142406). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Sep 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186498.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.L338F variant (also known as c.1012C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide … (more)
The p.L338F variant (also known as c.1012C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1012. The leucine at codon 338 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In another study, this variant was not detected in 60,466 breast cancer cases and seen in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Jun 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785220.2
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
|
|
|
Uncertain significance
(Mar 29, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000564874.5
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted CHEK2 c.1012C>T at the cDNA level, p.Leu338Phe (L338F) at the protein level, and results in the change of a Leucine to … (more)
This variant is denoted CHEK2 c.1012C>T at the cDNA level, p.Leu338Phe (L338F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu338Phe was not observed in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Leu338Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
|
|
|
Uncertain significance
(May 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047141.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Uncertain significance
(Jun 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001355158.2
First in ClinVar: Mar 25, 2020 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces leucine with phenylalanine at codon 338 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces leucine with phenylalanine at codon 338 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A yeast-based experimental functional assay demonstrated no impact to CHEK2 DNA damage repair activity (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020226.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
Comment:
Comment:
The p.L338F variant (also known as c.1012C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1012. The leucine at codon 338 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In another study, this variant was not detected in 60,466 breast cancer cases and seen in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This variant is denoted CHEK2 c.1012C>T at the cDNA level, p.Leu338Phe (L338F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu338Phe was not observed in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Leu338Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Comment:
This missense variant replaces leucine with phenylalanine at codon 338 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A yeast-based experimental functional assay demonstrated no impact to CHEK2 DNA damage repair activity (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 338 of the CHEK2 protein (p.Leu338Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with features of hereditary cancer (PMID: 31159747, 34326862). ClinVar contains an entry for this variant (Variation ID: 142406). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.L338F variant (also known as c.1012C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1012. The leucine at codon 338 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In another study, this variant was not detected in 60,466 breast cancer cases and seen in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This variant is denoted CHEK2 c.1012C>T at the cDNA level, p.Leu338Phe (L338F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu338Phe was not observed in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Leu338Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Comment:
This missense variant replaces leucine with phenylalanine at codon 338 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A yeast-based experimental functional assay demonstrated no impact to CHEK2 DNA damage repair activity (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Text-mined citations for rs587782441 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.