Submissions for variant NM_000535.7(PMS2):c.2534A>G (p.His845Arg)

dbSNP: rs1554292741

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000819801	SCV000960482	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-03-08	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 662202). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 845 of the PMS2 protein (p.His845Arg).
Ambry Genetics	RCV002427044	SCV002742431	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-11	criteria provided, single submitter	clinical testing	The p.H845R variant (also known as c.2534A>G), located in coding exon 15 of the PMS2 gene, results from an A to G substitution at nucleotide position 2534. The histidine at codon 845 is replaced by arginine, an amino acid with highly similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). Based on internal structural analysis, H845R disrupts the zinc-binding site of the endonuclease domain, a region sensitive to disruption (Gueneau E et al. Nat Struct Mol Biol, 2013 Apr;20:461-8). Another alteration at the same codon, p.H845L (c.2534A>T), has been detected in multiple probands whose Lynch-associated tumors demonstrated high microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (Goodenberger ML et al. Genet. Med., 2016 Jan;18:13-9; Yurgelun et al. J Clin Oncol 2017 Apr;35(10):1086-1095; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315255	SCV004012930	uncertain significance	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	2017-12-28	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV003453723	SCV004187583	likely pathogenic	Lynch syndrome 4	2023-09-25	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].