ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.506G>A (p.Arg169His)

gnomAD frequency: 0.00001  dbSNP: rs730881917
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160898 SCV000211592 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.506G>A at the cDNA level, p.Arg169His (R169H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Arg169His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. PMS2 Arg169His occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Arg169His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance
Ambry Genetics RCV000215633 SCV000274795 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-20 criteria provided, single submitter clinical testing The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected as germline in a breast cancer patient and as somatic in a colorectal cancer (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29; Dong L et al. Hum Mutat. 2018 Oct;39(10):1442-1455). 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 RCV000465290 SCV000551973 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-15 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 169 of the PMS2 protein (p.Arg169His). This variant is present in population databases (rs730881917, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and clinical features of Lynch syndrome (PMID: 30039884, 31433215). ClinVar contains an entry for this variant (Variation ID: 182811). 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%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 35451539). 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 RCV000215633 SCV000691079 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-17 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 169 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 31433215) and an individual affected with breast cancer (PMID: 30039884). This variant has been identified in 3/281050 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758687 SCV000887459 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.506G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Fulgent Genetics, Fulgent Genetics RCV000765966 SCV000897387 uncertain significance Mismatch repair cancer syndrome 1; Lynch syndrome 4 2018-10-31 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003416029 SCV004114393 uncertain significance PMS2-related condition 2023-06-22 criteria provided, single submitter clinical testing The PMS2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169His. This variant has been reported in a patient with Lynch syndrome (Okkels et al. 2019. PubMed ID: 31433215), an individual with breast cancer (Dong et al. 2018. PubMed ID: 30039884), and in a study of somatic mutations in tumors (Table S3, Shirts et al. 2018. PubMed ID: 29887214). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6042115-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182811/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc. RCV003454388 SCV004187565 likely pathogenic Lynch syndrome 4 2023-09-19 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics RCV003454388 SCV004205396 uncertain significance Lynch syndrome 4 2023-10-11 criteria provided, single submitter clinical testing

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