NM_007194.4(CHEK2):c.1215C>A (p.Asn405Lys) AND Familial cancer of breast

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 6, 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:: RCV000199599.21

Allele description [Variation Report for NM_007194.4(CHEK2):c.1215C>A (p.Asn405Lys)]

NM_007194.4(CHEK2):c.1215C>A (p.Asn405Lys)

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.1215C>A (p.Asn405Lys)

Other names:

p.N405K:AAC>AAA

HGVS:

NC_000022.11:g.28695754G>T
NG_008150.2:g.51113C>A
NM_001005735.2:c.1344C>A
NM_001257387.2:c.552C>A
NM_001349956.2:c.1014C>A
NM_007194.4:c.1215C>AMANE SELECT
NM_145862.2:c.1128C>A
NP_001005735.1:p.Asn448Lys
NP_001244316.1:p.Asn184Lys
NP_001336885.1:p.Asn338Lys
NP_009125.1:p.Asn405Lys
NP_665861.1:p.Asn376Lys
LRG_302t1:c.1215C>A
LRG_302:g.51113C>A
LRG_302p1:p.Asn405Lys
NC_000022.10:g.29091742G>T
NG_008150.1:g.51081C>A
NM_007194.3:c.1215C>A

Protein change:

N184K

Links:

dbSNP: rs587780171

NCBI 1000 Genomes Browser:

rs587780171

Molecular consequence:

NM_001005735.2:c.1344C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.552C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.1014C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1215C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1128C>A - 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
SCV000254920	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17100999, 28779002, 28492532
SCV000785786	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Dec 1, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17100999, 28779002 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004020174	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 9, 2023)	unknown	clinical testing	Citation Link,
SCV004215843	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 6, 2024)	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	unknown	unknown	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

Citations

PubMed

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

Evidence against a major genetic basis for combined breast and colorectal cancer susceptibility.

Brinkman H, Barwell J, Rose S, Tinworth L, Sodha N, Langman C, Brooks L, Payne S, Fisher S, Rowan A, Tomlinson I, Hodgson S.

Clin Genet. 2006 Dec;70(6):526-9. No abstract available.

PubMed [citation]

PMID:: 17100999

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000254920.13

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

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 405 of the CHEK2 protein (p.Asn405Lys). This variant is present in population databases (rs587780171, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or colon cancer (PMID: 17100999, 28779002). ClinVar contains an entry for this variant (Variation ID: 128050). 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 tolerated. 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 Counsyl, SCV000785786.2

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

#	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

From Myriad Genetics, Inc., SCV004020174.1

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

Description

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	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

From Baylor Genetics, SCV004215843.2

#	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 20, 2024

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