Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212854 | SCV000149617 | uncertain significance | not provided | 2022-06-22 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and/or ovarian cancer (Singh 2018); This variant is associated with the following publications: (PMID: 29470806, 11574484, Akbar2022[Abstract-poster]) |
Ambry Genetics | RCV000115708 | SCV000187600 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-06-28 | criteria provided, single submitter | clinical testing | The p.R294W variant (also known as c.880C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 880. The arginine at codon 294 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000168085 | SCV000218739 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 294 of the PMS2 protein (p.Arg294Trp). This variant is present in population databases (rs563433235, gnomAD 0.03%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 127799). 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 expected to disrupt PMS2 protein function. 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. |
Color Diagnostics, |
RCV000115708 | SCV000686250 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-08 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 294 of the PMS2 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 observed in an individual affected with breast and/or ovarian cancer (PMID: 29470806) and unaffected control individuals in a pancreatic cancer case-control study (PMID: 32980694). This variant has been identified in 12/282786 chromosomes 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. |
Myriad Genetics, |
RCV003315640 | SCV004020265 | likely benign | Lynch syndrome 4 | 2023-03-10 | criteria provided, single submitter | clinical testing | This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. |
Preventiongenetics, |
RCV003407498 | SCV004109762 | uncertain significance | PMS2-related condition | 2023-08-03 | criteria provided, single submitter | clinical testing | The PMS2 c.880C>T variant is predicted to result in the amino acid substitution p.Arg294Trp. This variant has been reported in an individual with breast and/or ovarian cancer (Table S4, Singh et al. 2018. PubMed ID: 29470806). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6035188-G-A). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127799/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |