NM_007194.4(CHEK2):c.1012C>T (p.Leu338Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Sep 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000131506.12

Allele description [Variation Report for NM_007194.4(CHEK2):c.1012C>T (p.Leu338Phe)]

NM_007194.4(CHEK2):c.1012C>T (p.Leu338Phe)

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.1012C>T (p.Leu338Phe)

HGVS:

NC_000022.11:g.28696984G>A
NG_008150.2:g.49883C>T
NM_001005735.2:c.1141C>T
NM_001257387.2:c.349C>T
NM_001349956.2:c.811C>T
NM_007194.4:c.1012C>TMANE SELECT
NM_145862.2:c.1009-1111C>T
NP_001005735.1:p.Leu381Phe
NP_001244316.1:p.Leu117Phe
NP_001336885.1:p.Leu271Phe
NP_009125.1:p.Leu338Phe
LRG_302t1:c.1012C>T
LRG_302:g.49883C>T
LRG_302p1:p.Leu338Phe
NC_000022.10:g.29092972G>A
NG_008150.1:g.49851C>T
NM_007194.3:c.1012C>T
p.L338F

Protein change:

L117F

Links:

dbSNP: rs587782441

NCBI 1000 Genomes Browser:

rs587782441

Molecular consequence:

NM_145862.2:c.1009-1111C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001005735.2:c.1141C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.349C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.811C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1012C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186498	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30851065, 31159747, 33471991 Citation Link,
SCV000821987	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001355158	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002537014	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 16, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 31159747, 33471991, 30851065 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

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.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000186498.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneKor MSA, SCV000821987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001355158.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002537014.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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