Submissions for variant NM_007194.4(CHEK2):c.239C>A (p.Pro80His)

dbSNP: rs876659006

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213858	SCV000274946	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	The p.P80H variant (also known as c.239C>A), located in coding exon 1 of the CHEK2 gene, results from a C to A substitution at nucleotide position 239. The proline at codon 80 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). In addition, this variant was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer. 2021 Jan;148(2):285-295). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542182	SCV000633159	uncertain significance	Familial cancer of breast	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 80 of the CHEK2 protein (p.Pro80His). 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: 231181). 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. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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.
Color Diagnostics, LLC DBA Color Health	RCV000213858	SCV001352375	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 80 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). A yeast-based assay has characterized this variant protein as functional (PMID: 30851065). 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.
Sema4, Sema4	RCV000213858	SCV002537411	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
Baylor Genetics	RCV000542182	SCV005058420	uncertain significance	Familial cancer of breast	2023-11-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001795353	SCV005079087	uncertain significance	not provided	2024-07-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect in a yeast-based growth assay (PMID: 30851065); Observed in an individual with sarcoma (PMID: 27498913); This variant is associated with the following publications: (PMID: 35643632, 30851065, 27498913)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001795353	SCV002034919	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001795353	SCV002035310	uncertain significance	not provided		no assertion criteria provided	clinical testing