Submissions for variant NM_000179.3(MSH6):c.2056G>T (p.Gly686Cys)

gnomAD frequency: 0.00001  dbSNP: rs1060502934

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460149	SCV000551251	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 686 of the MSH6 protein (p.Gly686Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 410509). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. This variant disrupts the p.Gly686 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18809606, 22949379, 25559809, 26552419, 26681312, 27273229, 28514183, 28531214, 28944238, 31965077; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775722	SCV000910142	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 686 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. Another variant that impacts this protein residue (MSH6 p.Gly686Asp) has been determined to be disease causing, indicating that this residue is important for MSH6 function (ClinVar Variation ID: 173071). This variant has not been identified 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.
Ambry Genetics	RCV000775722	SCV001174942	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	The p.G686C variant (also known as c.2056G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 2056. The glycine at codon 686 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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.
GeneDx	RCV001576673	SCV001803906	uncertain significance	not provided	2019-11-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Located in a critical functional domain: connector domain (Warren 2007, Kansikas 2011)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797726	SCV002041505	uncertain significance	not specified	2021-11-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001851	SCV004843768	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 686 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. Another variant that impacts this protein residue (MSH6 p.Gly686Asp) has been determined to be disease causing, indicating that this residue is important for MSH6 function (ClinVar Variation ID: 173071). This variant has not been identified 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.