ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1733G>A (p.Arg578His) (rs63750770)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199546 SCV000254608 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 578 of the PMS2 protein (p.Arg578His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs63750770, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual with prostate cancer (PMID: 29368341). ClinVar contains an entry for this variant (Variation ID: 216455). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000218135 SCV000274787 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-05 criteria provided, single submitter clinical testing The p.R578H variant (also known as c.1733G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1733. The arginine at codon 578 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in a breast cancer patient who underwent a 25 gene multi-gene panel test (Tung N et al. Cancer. 2015 Jan 1;121(1):25-33). Although one study looking at the effect of nuclear localization signals on nuclear import demonstrated that a missense mutation at residue R578 reduced nuclear localization, a subsequent study demonstrated no effect (Brieger A et al. Mol Carcinog. 2005 May;43(1):51-8; Leong V et al. Mol Carcinog. 2009 Aug;48(8):742-50). 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.
Color Health, Inc RCV000218135 SCV000686160 likely benign Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing
GeneDx RCV001544673 SCV001763847 uncertain significance not provided 2020-03-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with prostate cancer (Isaacsson Velho 2018); This variant is associated with the following publications: (PMID: 29596542, 29368341)

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