Submissions for variant NM_000179.3(MSH6):c.-2G>T

gnomAD frequency: 0.00003  dbSNP: rs374748889

Total submissions: 9

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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2023-06-30	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in a tumor sample from an individual with colorectal cancer (PMID: 34197922 (2021)). The frequency of this variant in the general population, 0.000015 (4/275398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000131214	SCV000910735	likely benign	Hereditary cancer-predisposing syndrome	2015-04-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818322	SCV002070924	uncertain significance	not specified	2021-08-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH6 gene demonstrated a homozygous sequence change in the 5’ UTR, c.-2G>T. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the East Asian subpopulation (dbSNP rs374748889). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. This change does not appear to have been previously described in individuals with MSH6-related disorders. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492616	SCV004239311	uncertain significance	Breast and/or ovarian cancer	2023-01-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532569	SCV004735006	likely benign	MSH6-related disorder	2019-05-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.