ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.880C>T (p.Arg294Trp)

gnomAD frequency: 0.00001  dbSNP: rs563433235
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, LLC DBA Color Health 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, Inc. 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, part of Exact Sciences 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.

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