Submissions for variant NM_007194.4(CHEK2):c.1374A>G (p.Lys458=)

gnomAD frequency: 0.00001  dbSNP: rs776093527

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480813	SCV000565725	uncertain significance	not provided	2016-09-29	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1374A>G at the DNA level. This variant is silent at the coding level, preserving a Lysine at codon 458. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. In silico splicing models are inconclusive; therefore, in the absence of RNA or functional studies, the actual effect of this variant is unknown. CHEK2 c.1374A>G 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.The nucleotide which is altered, a adenine (A) at base 1374, is not conserved. Based on currently available information, it is unclear whether CHEK2 c.1374A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000543380	SCV000633128	likely benign	Familial cancer of breast	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000560968	SCV000661695	likely benign	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000560968	SCV000689651	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	This synonymous variant causes an A to G nucleotide substitution 2 nucleotides upstream of the exon 12 splice donor site in the CHEK2 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250968 chromosomes 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.