ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.598G>A (p.Val200Ile)

dbSNP: rs730881704
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160456 SCV000211021 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.598G>A at the cDNA level, p.Val200Ile (V200I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Val200Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Val200Ile occurs at a position that is conserved in mammals and is located in the FHA domain (Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Val200Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000458835 SCV000550498 uncertain significance Familial cancer of breast 2022-10-16 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 200 of the CHEK2 protein (p.Val200Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 182456). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000570974 SCV000661711 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-16 criteria provided, single submitter clinical testing The p.V200I variant (also known as c.598G>A), located in coding exon 4 of the CHEK2 gene, results from a G to A substitution at nucleotide position 598. The valine at codon 200 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in 1/488 patients with stages I to III breast cancer diagnosed over age 50 who were tested with a 25-gene panel test, and p.V200I was classified as a variant of uncertain significance (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000570974 SCV000684670 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 200 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has not been identified 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.

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