Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000564219 | SCV000669898 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-06 | criteria provided, single submitter | clinical testing | The p.A53D variant (also known as c.158C>A), located in coding exon 1 of the MSH6 gene, results from a C to A substitution at nucleotide position 158. The alanine at codon 53 is replaced by aspartic acid, an amino acid with dissimilar properties. In a study of 63 cases of non-medullary thyroid cancer, this alteration was identified in one proband with sporadic papillary thyroid cancer who also carried an insertion in MSH6 (designated G56GPR). Both alterations were deemed likely benign, based on in silico predictions (Yu Y et al. Sci Rep, 2015 Nov;5:16129). 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. |
| Invitae | RCV001349167 | SCV001543497 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 53 of the MSH6 protein (p.Ala53Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with non-medullary thyroid, breast, or pancreatic cancer (PMID: 26530882, 35171259, 35449176). ClinVar contains an entry for this variant (Variation ID: 483762). 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. |
| All of Us Research Program, |
RCV004001046 | SCV004828108 | uncertain significance | Lynch syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with aspartic acid at codon 53 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 been reported in an individual affected with non-medullary thyroid cancer (PMID: 26530882). 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. |