NM_007194.4(CHEK2):c.170C>T (p.Ser57Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 9, 2024
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:: RCV000219585.12

Allele description [Variation Report for NM_007194.4(CHEK2):c.170C>T (p.Ser57Phe)]

NM_007194.4(CHEK2):c.170C>T (p.Ser57Phe)

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.170C>T (p.Ser57Phe)

Other names:

p.S57F:TCT>TTT

HGVS:

NC_000022.11:g.28734552G>A
NG_008150.2:g.12315C>T
NM_001005735.2:c.170C>T
NM_001257387.2:c.-608C>T
NM_001349956.2:c.170C>T
NM_007194.4:c.170C>TMANE SELECT
NM_145862.2:c.170C>T
NP_001005735.1:p.Ser57Phe
NP_001336885.1:p.Ser57Phe
NP_009125.1:p.Ser57Phe
NP_665861.1:p.Ser57Phe
LRG_302t1:c.170C>T
LRG_302:g.12315C>T
LRG_302p1:p.Ser57Phe
NC_000022.10:g.29130540G>A
NG_008150.1:g.12283C>T
NM_007194.3:c.170C>T

Protein change:

S57F

Links:

dbSNP: rs730881695

NCBI 1000 Genomes Browser:

rs730881695

Molecular consequence:

NM_001257387.2:c.-608C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.170C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.170C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.170C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.170C>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

Recent activity

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cytochrome b, partial (mitochondrion) [Taeniopoda centurio]
cytochrome b, partial (mitochondrion) [Taeniopoda centurio]
gi|1315891607|gb|AUG97936.1|

Protein
ODDD (0)
SRA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274859	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28709830, 30851065, 32255556, 37449874 Citation Link,
SCV000913607	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 14, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274859

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 9, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000913607

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 14, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2.

Schoolmeester JK, Moyer AM, Goodenberger ML, Keeney GL, Carter JM, Bakkum-Gamez JN.

Hum Pathol. 2017 Dec;70:14-26. doi: 10.1016/j.humpath.2017.06.018. Epub 2017 Jul 12.

PubMed [citation]

PMID:: 28709830

Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.

Delimitsou A, Fostira F, Kalfakakou D, Apostolou P, Konstantopoulou I, Kroupis C, Papavassiliou AG, Kleibl Z, Stratikos E, Voutsinas GE, Yannoukakos D.

Hum Mutat. 2019 May;40(5):631-648. doi: 10.1002/humu.23728. Epub 2019 Mar 9.

PubMed [citation]

PMID:: 30851065

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000274859.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.S57F variant (also known as c.170C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 170. The serine at codon 57 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was detected in conjunction with a pathogenic RAD51C mutation in an individual with early-onset breast cancer (Schoolmeester JK et al. Hum. Pathol., 2017 12;70:14-26). This alteration was also detected in an individual diagnosed with pancreatic cancer (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). 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 alteration was also reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). 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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000913607.3

#	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 serine with phenylalanine at codon 57 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study in yeast has shown this variant to be benign (PMID: 30851065). This variant has been reported in an individual affected with breast cancer, who also carried a pathogenic RAD51C variant (PMID: 28709830). This variant has been identified in 1/251454 chromosomes 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

Last Updated: Oct 20, 2024

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