Submissions for variant NM_000251.3(MSH2):c.-9G>C

gnomAD frequency: 0.00001  dbSNP: rs547444746

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160647	SCV000211249	benign	not specified	2014-08-11	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.
Counsyl	RCV000410517	SCV000488465	uncertain significance	Lynch syndrome 1	2016-04-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000732070	SCV000859965	uncertain significance	not provided	2018-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000732070	SCV000889446	uncertain significance	not provided	2019-05-08	criteria provided, single submitter	clinical testing
Invitae	RCV001850270	SCV002182050	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-17	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the MSH2 gene. It does not change the encoded amino acid sequence of the MSH2 protein. This variant is present in population databases (rs547444746, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182605). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000410517	SCV004018294	likely benign	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160647	SCV004020511	uncertain significance	not specified	2023-06-15	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.-9G>C is located in the untranslated mRNA region upstream of the initiation codon. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 151042 control chromosomes, predominantly at a frequency of 0.00031 within the African or African-American subpopulation in the gnomAD database. This frequency is somewhat lower than estimated maximum expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00057), allowing no clear conclusions about variant significance. To our knowledge, no occurrence of c.-9G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV003584558	SCV004359287	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 6/240592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003998488	SCV004822243	uncertain significance	Lynch syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 6/240592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.