Submissions for variant NM_000179.3(MSH6):c.2032G>C (p.Glu678Gln)

gnomAD frequency: 0.00002  dbSNP: rs751778243

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213514	SCV000273409	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	The p.E678Q variant (also known as c.2032G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 2032. The glutamic acid at codon 678 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 Nov;29:1381-1389). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000529803	SCV000624718	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213514	SCV000908387	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 678 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 5/250724 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985829	SCV001134404	uncertain significance	not provided	2018-09-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468992	SCV004197579	uncertain significance	Endometrial carcinoma	2023-10-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997791	SCV004843735	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 678 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 5/250724 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.