Submissions for variant NM_000535.7(PMS2):c.218G>A (p.Cys73Tyr)

dbSNP: rs1326865470

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000556750	SCV000625598	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-04-28	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 455691). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 73 of the PMS2 protein (p.Cys73Tyr).
Genetic Services Laboratory, University of Chicago	RCV001821472	SCV002067474	uncertain significance	not specified	2020-04-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.218G>A, in exon 3 that results in an amino acid change, p.Cys73Tyr. This sequence change has been described in the gnomaD database with a low population frequency of 0.00039% (dbSNP rs1326865470). The p.Cys73Tyr change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys73Tyr substitution. This sequence change does not appear to have been previously reported in patients with PMS2-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Cys73Tyr change remains unknown at this time.
Sema4, Sema4	RCV002255430	SCV002530272	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	curation
Ambry Genetics	RCV002255430	SCV002724901	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	clinical testing	The p.C73Y variant (also known as c.218G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 218. The cysteine at codon 73 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well 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.
PreventionGenetics, part of Exact Sciences	RCV003392363	SCV004110001	uncertain significance	PMS2-related condition	2023-02-16	criteria provided, single submitter	clinical testing	The PMS2 c.3G>A variant is predicted to disrupt the translation initiation site (Start Loss). This variant corresponds to a missense change in he primary PMS2 transcript (NM_000535.6:c.218G>A, p.Cys73Tyr). To our knowledge, this variant has not been reported in the literature. This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/7-6043635-C-T). It is interpreted as uncertain significance in CllinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/455691/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.