Submissions for variant NM_000535.7(PMS2):c.1632C>A (p.Asp544Glu)

dbSNP: rs786203439

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166744	SCV000217555	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The p.D544E variant (also known as c.1632C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1632. The aspartic acid at codon 544 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000525179	SCV000625544	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 544 of the PMS2 protein (p.Asp544Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 187057). 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 not 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.
Color Diagnostics, LLC DBA Color Health	RCV000166744	SCV000691034	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 544 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 1/250936 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.
GeneDx	RCV003332134	SCV004039782	uncertain significance	not provided	2023-09-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with colorectal cancer (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 28135145)