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

gnomAD frequency: 0.00001  dbSNP: rs369763423

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212855	SCV000149618	uncertain significance	not provided	2024-11-21	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; This variant is associated with the following publications: (PMID: 35449176, 11574484, 33471991, 27978560)
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549353	SCV000625706	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-27	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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689611	SCV005184549	uncertain significance	not specified	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.884G>A (p.Arg295Gln) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.884G>A has been reported in the literature in the heterozygous state in individuals affected with breast cancer (e.g. Hu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35449176). ClinVar contains an entry for this variant (Variation ID: 127800). Based on the evidence outlined above, the variant was classified as uncertain significance.