Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000800549 | SCV000940273 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-09-02 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with cysteine at codon 521 of the MSH2 protein (p.Tyr521Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. |
Ambry Genetics | RCV002397611 | SCV002708728 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-04-22 | criteria provided, single submitter | clinical testing | The p.Y521C variant (also known as c.1562A>G), located in coding exon 10 of the MSH2 gene, results from an A to G substitution at nucleotide position 1562. The tyrosine at codon 521 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not 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. |
Baylor Genetics | RCV003467383 | SCV004196264 | uncertain significance | Lynch syndrome 1 | 2023-09-08 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004001635 | SCV004833482 | uncertain significance | Lynch syndrome | 2023-07-10 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 521 of the MSH2 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 MSH2-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. |