Submissions for variant NM_000535.7(PMS2):c.884G>A (p.Arg295Gln)

gnomAD frequency: 0.00001  dbSNP: rs369763423

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212855	SCV000149618	uncertain significance	not provided	2022-08-17	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: 11574484)
Ambry Genetics	RCV000115709	SCV000184620	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-31	criteria provided, single submitter	clinical testing	The p.R295Q variant (also known as c.884G>A), located in coding exon 8 of the PMS2 gene, results from a G to A substitution at nucleotide position 884. The arginine at codon 295 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a 47-year-old patient with colorectal cancer that demonstrated proficient immunohistochemical (IHC) staining for all mismatch repair genes (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This variant was also reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000549353	SCV000625706	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 295 of the PMS2 protein (p.Arg295Gln). This variant is present in population databases (rs369763423, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). ClinVar contains an entry for this variant (Variation ID: 127800). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000115709	SCV000904180	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 295 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 an individual affected with colorectal cancer (PMID: 27978560). In a large breast cancer case-control study, this variant was reported in 2/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251372 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.
Baylor Genetics	RCV003467057	SCV004207798	uncertain significance	Lynch syndrome 4	2023-07-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997294	SCV004839888	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 295 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 an individual affected with colorectal cancer (PMID: 27978560). In a large breast cancer case-control study, this variant was reported in 2/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251372 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.