Submissions for variant NM_000179.3(MSH6):c.457+7G>C

gnomAD frequency: 0.00001  dbSNP: rs781280171

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425768	SCV000516627	likely benign	not specified	2016-11-29	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.
Invitae	RCV000467549	SCV000561442	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580489	SCV000685492	likely benign	Hereditary cancer-predisposing syndrome	2016-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000425768	SCV000917750	uncertain significance	not specified	2017-12-07	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.457+7G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing (though one tool predicts the disappearance of a cryptic acceptor site). ESE finder predicts that this variant may affect the binding site of the splicing factor SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4/245942 control chromosomes at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). This variant co-occurrs with a likely pathogenic variant MSH6 c.1610_1613delAGTA in an internal specimen. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Because of the absence of clinical information and the lack of functional studies, the variant is classified as VUS-possibly benign, until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477916	SCV004222041	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000026 (3/113468 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MSH6 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.