ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2458+8C>G (rs189025757)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122985 SCV000166273 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000411107 SCV000489490 likely benign Lynch syndrome I 2016-10-11 criteria provided, single submitter clinical testing
GeneDx RCV000202181 SCV000513665 likely benign not specified 2017-07-20 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 RCV000580893 SCV000685046 likely benign Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202181 SCV000919708 uncertain significance not specified 2017-12-22 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2458+8C>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17/276928 control chromosomes (gnomAD) at a frequency of 0.0000614, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign, while one clinical diagnostic laboratory classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. However, an internal LCA sample reports the variant to co-occur with a pathogenic TP53 variant, c.637C>T (p.Arg213X). Therefore, due the relative frequent occurrences in the controls (although doesn't exceed maximal expected), nature of variant being intronic with no predicted effect on splicing, co-occurrence with a pathogenic TP53 variant, and clinical diagnostic laboratories classifications of "likely benign," the variant is classified as a "Variant of Uncertain Significance - Possibly Benign."
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202181 SCV000257177 uncertain significance not specified no assertion criteria provided research

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