NM_007194.4(CHEK2):c.134C>T (p.Thr45Met) AND Familial cancer of breast

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 21, 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:: RCV000230142.16

Allele description [Variation Report for NM_007194.4(CHEK2):c.134C>T (p.Thr45Met)]

NM_007194.4(CHEK2):c.134C>T (p.Thr45Met)

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.134C>T (p.Thr45Met)

HGVS:

NC_000022.11:g.28734588G>A
NG_008150.2:g.12279C>T
NM_001005735.2:c.134C>T
NM_001257387.2:c.-644C>T
NM_001349956.2:c.134C>T
NM_007194.4:c.134C>TMANE SELECT
NM_145862.2:c.134C>T
NP_001005735.1:p.Thr45Met
NP_001336885.1:p.Thr45Met
NP_009125.1:p.Thr45Met
NP_665861.1:p.Thr45Met
LRG_302t1:c.134C>T
LRG_302:g.12279C>T
LRG_302p1:p.Thr45Met
NC_000022.10:g.29130576G>A
NG_008150.1:g.12247C>T
NM_007194.3:c.134C>T

Protein change:

T45M

Links:

dbSNP: rs558321010

NCBI 1000 Genomes Browser:

rs558321010

Molecular consequence:

NM_001257387.2:c.-644C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000289662	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26580448, 28492532
SCV004215855	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 18, 2023)	unknown	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

SCV000289662

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2024)

germline

clinical testing

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

SCV004215855

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 18, 2023)

unknown

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000289662.10

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 45 of the CHEK2 protein (p.Thr45Met). This variant is present in population databases (rs558321010, gnomAD 0.01%). This missense change has been observed in individual(s) with pediatric acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 230559). 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.

#	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 Baylor Genetics, SCV004215855.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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