Submissions for variant NM_000535.7(PMS2):c.142G>A (p.Asp48Asn)

dbSNP: rs755665894

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220384	SCV000277905	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	The p.D48N variant (also known as c.142G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 142. The aspartic acid at codon 48 is replaced by asparagine, an amino acid with highly similar properties. This alteration is detected in at least one individual whose Lynch-related tumor demonstrated microsatellite stability and/or normal mismatch repair protein expression on immunohistochemistry (Ambry internal data). This alteration was also seen to co-segregate in a family that meets Amsterdam criteria (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 conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000549401	SCV000625527	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 48 of the PMS2 protein (p.Asp48Asn). This variant is present in population databases (rs755665894, gnomAD 0.0009%). 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: 233518). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780615	SCV000918034	uncertain significance	not specified	2017-10-31	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.142G>A (p.Asp48Asn) variant involves the alteration of a conserved nucleotide that lies within the histidine kinase/HSP90-like ATPase domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/240414 control chromosomes at a frequency of 0.0000042, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). One clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985901	SCV001134579	uncertain significance	not provided	2019-07-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000985901	SCV004223994	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	PP3, PM2
All of Us Research Program, National Institutes of Health	RCV003998560	SCV004841933	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 48 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with a Lynch syndrome-associated cancer that demonstrated microsatellite stability and/or intact mismatch repair protein expression via immunohistochemistry analysis (ClinVar SCV000277905.6). This variant has been identified in 1/245776 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.