ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.907T>C (p.Leu303=) (rs752359705)

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Total submissions: 5
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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 Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign
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 RCV000163350 SCV000684695 likely benign Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 RCV000587452 SCV000757042 likely benign not provided 2019-02-18 criteria provided, single submitter clinical testing

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