NM_007194.4:c.38A>G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_007194.4(CHEK2):c.38A>G(p.His13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces histidine with arginine at codon 13 of the CHEK2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported in one individual affected with personal history and family history of breast cancer and adenosarcoma (PMID: 21562711). Functional studies have shown that the variant does not affect catalytic activity or stability of the CHEK2 protein (PMID: 21562711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Uncertain:1
This variant is denoted CHEK2 c.38A>G at the cDNA level, p.His13Arg (H13R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Although this variant was observed in a patient with bilateral breast cancer and a uterine sarcoma, functional assays demonstrated the resultant protein's properties as comparable to wild-type (Manoukian 2011). CHEK2 His13Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 His13Arg occurs at a position that is conserved across mammals, with Arginine being the naturally occurring amino acid at this position in two species, and is not located in a known functional domain (Desrichard 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CHEK2 His13Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Familial cancer of breast Uncertain:1
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 13 of the CHEK2 protein (p.His13Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or sarcoma (PMID: 21562711). ClinVar contains an entry for this variant (Variation ID: 418613). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 21562711). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at