NM_007194.4(CHEK2):c.164C>T (p.Ser55Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 14, 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:: RCV000574842.11

Allele description [Variation Report for NM_007194.4(CHEK2):c.164C>T (p.Ser55Phe)]

NM_007194.4(CHEK2):c.164C>T (p.Ser55Phe)

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.164C>T (p.Ser55Phe)

HGVS:

NC_000022.11:g.28734558G>A
NG_008150.2:g.12309C>T
NM_001005735.2:c.164C>T
NM_001257387.2:c.-614C>T
NM_001349956.2:c.164C>T
NM_007194.4:c.164C>TMANE SELECT
NM_145862.2:c.164C>T
NP_001005735.1:p.Ser55Phe
NP_001336885.1:p.Ser55Phe
NP_009125.1:p.Ser55Phe
NP_665861.1:p.Ser55Phe
LRG_302t1:c.164C>T
LRG_302:g.12309C>T
LRG_302p1:p.Ser55Phe
NC_000022.10:g.29130546G>A
NG_008150.1:g.12277C>T
NM_007194.3:c.164C>T

Protein change:

S55F

Links:

dbSNP: rs765799649

NCBI 1000 Genomes Browser:

rs765799649

Molecular consequence:

NM_001257387.2:c.-614C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.164C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.164C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.164C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.164C>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
SCV000666365	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22006311, 26580448, 31871109, 32832836 Citation Link,
SCV001339935	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22006311, 31871109, 25741868
SCV002537406	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 25, 2022)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 31871109, 22006311 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000666365

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 14, 2023)

germline

clinical testing

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

Citation Link,

SCV001339935

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 13, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002537406

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 25, 2022)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

Matejcic M, Patel Y, Lilyquist J, Hu C, Lee KY, Gnanaolivu RD, Hart SN, Polley EC, Yadav S, Boddicker NJ, Samara R, Xia L, Sheng X, Lubmawa A, Kiddu V, Masaba B, Namuguzi D, Mutema G, Job K, Henry DM, Ingles SA, Wilkens L, et al.

JCO Precis Oncol. 2020;4:32-43. doi: 10.1200/po.19.00179. Epub 2020 Jan 31.

PubMed [citation]

PMID:: 32832836
PMCID:: PMC7442213

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000666365.6

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

Description

The p.S55F variant (also known as c.164C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 164. The serine at codon 55 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Walsh T et al. Proc Natl Acad Sci U S A, 2011 Nov;108:18032-7; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). In addition, this variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M. JCO Precis Oncol . 2020 Jan;4:32-43). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a high grade glioma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is well 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, SCV001339935.3

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

Description

This missense variant replaces serine with phenylalanine at codon 55 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 has shown the mutant protein to exhibit near normal activity in a yeast-based DNA damage repair / complementation assay (PMID: 22006311). This variant has been reported in an individual affected with a carcinoma of ovarian, fallopian tube, or peritoneal origin in the literature (PMID: 22006311) and in an individual affected with breast cancer who also carried a pathogenic variant in the BRCA2 gene (PMID: 31871109). This variant has been identified in 2/251444 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

From Sema4, Sema4, SCV002537406.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

#	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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