VCV000232564.23 - ClinVar

NM_007194.4(CHEK2):c.1032A>G (p.Ile344Met)

Germline

Classification

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.

(6)

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

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.1032A>G (p.Ile344Met)

Variation ID: 232564 Accession: VCV000232564.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.1 22: 28696964 (GRCh38) [ NCBI UCSC ] 22: 29092952 (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	May 29, 2016	Sep 16, 2024	Jan 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1032A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Ile344Met	missense
NM_001005735.2:c.1161A>G	NP_001005735.1:p.Ile387Met	missense
NM_001257387.2:c.369A>G	NP_001244316.1:p.Ile123Met	missense
NM_001349956.2:c.831A>G	NP_001336885.1:p.Ile277Met	missense
NM_145862.2:c.1009-1091A>G		intron variant
NC_000022.11:g.28696964T>C
NC_000022.10:g.29092952T>C
NG_008150.2:g.49903A>G
LRG_302:g.49903A>G
LRG_302t1:c.1032A>G	LRG_302p1:p.Ile344Met

... more HGVS ... less HGVS

Protein change

I344M, I123M, I277M, I387M

Other names

Canonical SPDI

NC_000022.11:28696963:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA10167741 dbSNP: rs202051128 VarSome

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
Gene	OMIM	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	4053	4109

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 20, 2023	RCV000214665.14
Familial cancer of breast	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 14, 2024	RCV000807751.16
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000759771.17

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 (Dec 08, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889321.4 First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 30287823 Comment: The frequency of this variant in the general population, 0.00035 (7/19946 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.00035 (7/19946 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer as well as in several healthy controls (PMID: 30287823 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Jun 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000276727.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 30287823‚ 30826992‚ 33471991 Comment: The p.I344M variant (also known as c.1032A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide … (more) The p.I344M variant (also known as c.1032A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1032. The isoleucine at codon 344 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported with a carrier frequency of 0.00057 in 7,051 unselected breast cancer patients and 0.00036 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been reported in 1/416 papillary thyroid carcinoma patients and 0/100 healthy controls (Shen CT et al. Endocrine, 2019 06;64:622-631). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jan 04, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567295.7 First in ClinVar: Apr 29, 2017 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22419737, 19782031, 30826992, 33471991, 36243179, 30287823) (less)
Uncertain significance (Dec 12, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001351703.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Uncertain significance (Jan 14, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000947822.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30287823 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 344 of the CHEK2 protein (p.Ile344Met). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 344 of the CHEK2 protein (p.Ile344Met). This variant is present in population databases (rs202051128, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 232564). 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. 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 (Dec 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005058410.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

The frequency of this variant in the general population, 0.00035 (7/19946 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer as well as in several healthy controls (PMID: 30287823 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

The p.I344M variant (also known as c.1032A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1032. The isoleucine at codon 344 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported with a carrier frequency of 0.00057 in 7,051 unselected breast cancer patients and 0.00036 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been reported in 1/416 papillary thyroid carcinoma patients and 0/100 healthy controls (Shen CT et al. Endocrine, 2019 06;64:622-631). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22419737, 19782031, 30826992, 33471991, 36243179, 30287823)

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 344 of the CHEK2 protein (p.Ile344Met). This variant is present in population databases (rs202051128, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 232564). 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. 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Targeted next-generation sequencing in papillary thyroid carcinoma patients looking for germline variants predisposing to the disease.	Shen CT	Endocrine	2019	PMID: 30826992
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.	Momozawa Y	Nature communications	2018	PMID: 30287823

Text-mined citations for rs202051128 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_007194.4(CHEK2):c.1032A>G (p.Ile344Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202051128 ...