Submissions for variant NM_000535.7(PMS2):c.2144A>C (p.His715Pro)

dbSNP: rs773913260

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001203561	SCV001374734	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 715 of the PMS2 protein (p.His715Pro). 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 variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 935055). 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.
GeneDx	RCV002298901	SCV002588106	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Fukui2011[Chapter])
Ambry Genetics	RCV002429869	SCV002729286	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	clinical testing	The p.H715P variant (also known as c.2144A>C), located in coding exon 12 of the PMS2 gene, results from an A to C substitution at nucleotide position 2144. The histidine at codon 715 is replaced by proline, 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.
Color Diagnostics, LLC DBA Color Health	RCV002429869	SCV004359545	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 715 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/238398 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002298901	SCV004565103	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	The PMS2 c.2144A>C; p.His715Pro variant (rs773913260), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 935055). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.672). Due to limited information, the clinical significance of this variant is uncertain at this time.