NM_007194.4(CHEK2):c.539G>A (p.Arg180His) AND Hereditary cancer-predisposing syndrome - ClinVar (2024)

Somatic classification
of clinical impact:

None

Review status:

(0/4)

no assertion criteria provided

Somatic classification
of oncogenicity:

None

Review status:

(0/4)

no assertion criteria provided

NM_007194.4(CHEK2):c.539G>A (p.Arg180His)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

• Chr22: 28725030 (on Assembly GRCh38)
• Chr22: 29121018 (on Assembly GRCh37)

Preferred name:

NM_007194.4(CHEK2):c.539G>A (p.Arg180His)

Other names:

p.R180H:CGC>CAC

HGVS:

• NC_000022.11:g.28725030C>T
• NG_008150.2:g.21837G>A
• NM_001005735.2:c.668G>A
• NM_001257387.2:c.-239G>A
• NM_001349956.2:c.445-107G>A
• NM_007194.4:c.539G>AMANE SELECT
• NM_145862.2:c.539G>A
• NP_001005735.1:p.Arg223His
• NP_009125.1:p.Arg180His
• NP_665861.1:p.Arg180His
• LRG_302t1:c.539G>A
• LRG_302:g.21837G>A
• LRG_302p1:p.Arg180His
• NC_000022.10:g.29121018C>T
• NG_008150.1:g.21805G>A
• NM_001005735.2:c.668G>A
• NM_007194.3:c.539G>A
• O96017:p.Arg180His
• p.R180H

Protein change:

R180H; ARG180HIS

Links:

UniProtKB: O96017#VAR_019110; OMIM: 604373.0007; dbSNP: rs137853009

NCBI 1000 Genomes Browser:

rs137853009

Molecular consequence:

• NM_001257387.2:c.-239G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
• NM_001349956.2:c.445-107G>A - intron variant - [Sequence Ontology: SO:0001627]
• NM_001005735.2:c.668G>A - missense variant - [Sequence Ontology: SO:0001583]
• NM_007194.4:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
• NM_145862.2:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]

Description

The p.R180H variant (also known as c.539G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 539. The arginine at codon 180 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in individuals diagnosed with breast, prostate, and colorectal cancer (Sodha N et al. Br. J. Cancer. 2002 Dec;87:1445-8; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Greville-Heygate SL et al. JCO Precis Oncol, 2020 May;4:). Functional analyses of the p.R180H allele have supported pathogenicity, with most studies demonstrating low or intermediate levels of functional impairment (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer, 2019 10;145:1782-1797; Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by silico analyses. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.