Submissions for variant NM_007194.4(CHEK2):c.907T>C (p.Leu303=)

dbSNP: rs752359705

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163350	SCV000213884	likely benign	Hereditary cancer-predisposing syndrome	2015-09-15	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.
GeneDx	RCV000429216	SCV000530287	likely benign	not specified	2016-07-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000163350	SCV000684695	likely benign	Hereditary cancer-predisposing syndrome	2016-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587452	SCV000698821	benign	not provided	2017-06-23	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.907T>C (p.Leu303Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 13 of 29770 control chromosomes (1 homozygote), but was observed exclusively in the South Asian subpopulation at a frequency of 0.001524 (13/8528; 1 homozygote). This frequency is about 54 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), strongly suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. Although this site has been successfully tested in a reduced number of control individuals in ExAC, the large control database gnomAD supports this finding with a larger number of samples tested (22/196838 control chromosomes [1 homozygote]; South Asian frequency of 21/26240 [1 homozygote]). In addition, two clinical diagnostic laboratories have classified this variant as likely benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Invitae	RCV001086645	SCV000757042	likely benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000429216	SCV004024646	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing