Submissions for variant NM_007194.4(CHEK2):c.462C>G (p.Asn154Lys)

dbSNP: rs564924749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565060	SCV000661747	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-13	criteria provided, single submitter	clinical testing	The p.N154K variant (also known as c.462C>G), located in coding exon 3 of the CHEK2 gene, results from a C to G substitution at nucleotide position 462. The asparagine at codon 154 is replaced by lysine, an amino acid with similar properties. This amino acid position is well 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	RCV000565060	SCV000689689	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589429	SCV000698802	uncertain significance	not provided	2017-03-16	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.462C>G (p.Asn154Lys) variant located in the SMAD/FHA domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121336 (1/60668), which does not exceed the estimated maximal expected allele frequency for a pathogenic CHEK2 variant of 1/35211. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae	RCV001066693	SCV001231709	uncertain significance	Familial cancer of breast	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 154 of the CHEK2 protein (p.Asn154Lys). This variant is present in population databases (rs564924749, gnomAD 0.01%). 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: 479564). 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 tolerated. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357483	SCV001552967	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Asn154Lys variant was not identified in the literature. The variant was identified in dbSNP (ID: rs564924749) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics, Color and one clinical laboratory). The variant was identified in control databases in 3 of 246208 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 3 of 30782 chromosomes (freq: 0.00009), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Asn154 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.