Submissions for variant NM_000535.7(PMS2):c.2567T>G (p.Leu856Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782342

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131279	SCV000186247	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The p.L856R variant (also known as c.2567T>G), located in coding exon 15 of the PMS2 gene, results from a T to G substitution at nucleotide position 2567. The leucine at codon 856 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in an early onset rectal cancer with absent staining of MSH6 and PMS2 on IHC. This variant has also been detected in conjunction with a pathogenic mutation in PMS2 by our laboratory; however, the phase (whether in cis or trans) is not known. The patient's phenotype was suggestive of CMMR-D (Ambry internal data). 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	RCV000467305	SCV000551965	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-30	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 142260). 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. 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. This missense change has been observed in individuals with colon cancer and/or endometrial cancer (Invitae). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 856 of the PMS2 protein (p.Leu856Arg). 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.
GeneDx	RCV001596973	SCV001830840	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with cancer evaluated with MSI and IHC (Li et al., 2020); This variant is associated with the following publications: (PMID: Fukui2011[Chapter], 31391288)
Sema4, Sema4	RCV000131279	SCV002530319	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	curation
GenomeConnect - Invitae Patient Insights Network	RCV001535447	SCV001749358	not provided	Mismatch repair cancer syndrome 1; Lynch syndrome 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.