Submissions for variant NM_000535.7(PMS2):c.508C>A (p.His170Asn)

dbSNP: rs876661152

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213923	SCV000279672	uncertain significance	not provided	2015-12-03	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.508C>A at the cDNA level, p.His170Asn (H170N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 His170Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 His170Asn occurs at a position that is not conserved and is located in the ATPase domain (Fukui 2011, Guarne 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 His170Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699509	SCV000828222	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 170 of the PMS2 protein (p.His170Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234669). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV001023516	SCV001185414	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-20	criteria provided, single submitter	clinical testing	The p.H170N variant (also known as c.508C>A), located in coding exon 5 of the PMS2 gene, results from a C to A substitution at nucleotide position 508. The histidine at codon 170 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well 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.