Submissions for variant NM_000179.3(MSH6):c.3966A>T (p.Glu1322Asp)

gnomAD frequency: 0.00001  dbSNP: rs1064794745

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479559	SCV000569861	uncertain significance	not provided	2017-01-11	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3966A>T at the cDNA level, p.Glu1322Asp (E1322D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu1322Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MSH6 Glu1322Asp occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located within the MutS domain V and binding sites of MSH2 (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Glu1322Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000814519	SCV000954932	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1322 of the MSH6 protein (p.Glu1322Asp). 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: 420855). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001186883	SCV001353476	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1322 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
PreventionGenetics, part of Exact Sciences	RCV004535514	SCV004117365	uncertain significance	MSH6-related disorder	2023-07-24	criteria provided, single submitter	clinical testing	The MSH6 c.3966A>T variant is predicted to result in the amino acid substitution p.Glu1322Asp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/420855/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003337	SCV004835177	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1322 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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	RCV001186883	SCV005033381	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-30	criteria provided, single submitter	clinical testing	The p.E1322D variant (also known as c.3966A>T), located in coding exon 9 of the MSH6 gene, results from an A to T substitution at nucleotide position 3966. The glutamic acid at codon 1322 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated normal mismatch repair protein expression by immunohistochemistry (Ambry internal data). This amino acid position is well conserved through mammals but not in all 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.