Submissions for variant NM_007194.4(CHEK2):c.429C>G (p.His143Gln)

dbSNP: rs1555927151

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566903	SCV000676011	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-31	criteria provided, single submitter	clinical testing	The p.H143Q variant (also known as c.429C>G), located in coding exon 2 of the CHEK2 gene, results from a C to G substitution at nucleotide position 429. The histidine at codon 143 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000566903	SCV001347605	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-09	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 143 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483678	SCV004228266	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-11	criteria provided, single submitter	curation	PM2_sup, PM5_sup, PP3. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from gnomAD, PM5 (supporting pathogenic): AS position seems to be crucial vor protein function but functional data for this variant is missing, PP3 (supporting pathogenic): In silico prediction mainly loss of function
Invitae	RCV003500567	SCV004306663	uncertain significance	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 143 of the CHEK2 protein (p.His143Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 486839). 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.