Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002230106 | SCV000551092 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-04-05 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 742 of the MSH6 protein (p.Asn742Ser). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 410422). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). This variant is not present in population databases (gnomAD no frequency). |
Ambry Genetics | RCV002429525 | SCV002730215 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-05-25 | criteria provided, single submitter | clinical testing | The p.N742S variant (also known as c.2225A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2225. The asparagine at codon 742 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). 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. |
All of Us Research Program, |
RCV004001825 | SCV004841850 | uncertain significance | Lynch syndrome | 2023-03-04 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with serine at codon 742 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 been reported in an individual affected with breast cancer (PMID: 26976419). 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. |