ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.-2G>T (rs374748889)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131214 SCV000186165 likely benign Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing Other data supporting benign classification
GeneDx RCV000588323 SCV000211375 likely benign not provided 2021-09-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26888055)
Invitae RCV000199508 SCV000254236 uncertain significance Lynch syndrome 2015-06-13 criteria provided, single submitter clinical testing This sequence change falls in the 5' UTR promoter region of the MSH6 gene. It does not change the encoded amino acid sequence of the MSH6 protein. This variant has not been published in the literature and is present in population databases (rs374748889, 0.02%). ClinVar contains an entry for this variant (RCV000131214). In summary, this is a rare 5' non-coding change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588323 SCV000601552 uncertain significance not provided 2019-03-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588323 SCV000695836 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.-2G>T variant located in the Kozak sequence of MSH6 involves the alteration of a non-conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the loss of a canonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/115448 control chromosomes at a frequency of 0.0000173, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as 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. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Health, Inc RCV000131214 SCV000910735 likely benign Hereditary cancer-predisposing syndrome 2015-04-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000199508 SCV000592560 uncertain significance Lynch syndrome no assertion criteria provided clinical testing MSH6, EXON1, c.-2G>T, r.(spl)?, Heterozygous, Uncertain Significance The MSH6 c.-2G>T variant was not identified in the literature in an affected population. The variant was identified in dbSNP (ID: rs374748889 as “With other allele”) and ClinVar (classified as likely benign by GeneDx and classified as uncertain significance by Ambry Genetics, Invitae, COGR, Quest Diagnostics, and Integrated Genetics). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database or Insight Hereditary Tumors database. The variant was identified in control databases in 5 of 270534 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6350 chromosomes (freq: 0.0002), East Asian in 3 of 18528 chromosomes (freq: 0.0002), and South Asian in 1 of 30416 chromosomes (freq: 0.00003); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish or Finnish populations. The variant was previously identified by our laboratory in 1 individual with endometrial and ovarian cancer as co-occurring with a pathogenic PMS2 variant (c.2500_2501delinsG, p.Met834Glyfs*17), increasing the likelihood that the MSH6 c.-2G>T variant does not have clinical significance. The variant is located in the MSH6 promoter region (Liu 2016), which could result in reduced gene expression but further study would be needed to confirm this. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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