Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000574035 | SCV000676181 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-09-02 | criteria provided, single submitter | clinical testing | The p.C812Y variant (also known as c.2435G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2435. The cysteine at codon 812 is replaced by tyrosine, an amino acid with highly dissimilar 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 5207 samples (10414 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. 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. |
| Invitae | RCV000796087 | SCV000935582 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2018-07-24 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 486934). This sequence change replaces cysteine with tyrosine at codon 812 of the PMS2 protein (p.Cys812Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. The frequency data for this variant in the population databases (rs876661116, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. |