ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.452G>A (p.Arg151His)

gnomAD frequency: 0.00001  dbSNP: rs35629870
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766584 SCV000211589 uncertain significance not provided 2023-03-06 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21153778, 19389263, 11574484, 31857677, 29752822, 20698049)
Invitae RCV000456758 SCV000551995 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 151 of the PMS2 protein (p.Arg151His). This variant is present in population databases (rs35629870, gnomAD 0.006%). This missense change has been observed in individual(s) with Lynch syndrome and breast cancer (PMID: 20698049, 29752822, 35449176). ClinVar contains an entry for this variant (Variation ID: 156510). 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 with a positive predictive value of 80%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160896 SCV000601850 uncertain significance not specified 2017-02-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561546 SCV000670802 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-13 criteria provided, single submitter clinical testing The p.R151H variant (also known as c.452G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 452. The arginine at codon 151 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in 1/937 unselected Chinese breast cancer patients and in 10/26 Chinese patients who met at least Bethesda guidelines for Lynch syndrome (Sheng X et al. World J. Gastroenterol. 2010 Aug;16(30):3847-52; Li JY et al. Int J Cancer. 2019 Jan 15;144(2):281-289). This alteration was identified in a cohort of Chinese breast cancer patients (Chen B et al. Aging (Albany NY), 2020 Feb;12:3140-3155). 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.
Color Diagnostics, LLC DBA Color Health RCV000561546 SCV000903602 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 151 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 10 of 26 Chinese individuals affected with Lynch syndrome (PMID: 20698049) and in a Chinese breast/ovarian cancer case (PMID: 32068069). This variant has been identified in 3/250806 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.
Baylor Genetics RCV003462055 SCV004205495 uncertain significance Lynch syndrome 4 2023-08-03 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144643 SCV000189970 uncertain significance Lynch syndrome 1 2014-07-24 no assertion criteria provided clinical testing

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