Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000167175 | SCV000218008 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-12-30 | criteria provided, single submitter | clinical testing | The p.E1348D variant (also known as c.4044A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4044. The glutamic acid at codon 1348 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 42000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.003 (Terui H et al. J. Biomed. Sci. 2013;20:25). Since supporting evidence is limited at this time, the clinical significance of p.E1348D remains unclear. |
| Invitae | RCV000803004 | SCV000942857 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-29 | 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 1348 of the MSH6 protein (p.Glu1348Asp). 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: 187446). 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%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265650 | SCV002547894 | uncertain significance | not specified | 2022-05-30 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003995569 | SCV004831918 | uncertain significance | Lynch syndrome | 2023-06-08 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 1348 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 MSH6-related disorders 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. |