Submissions for variant NM_000535.7(PMS2):c.1262G>A (p.Arg421Gln)

gnomAD frequency: 0.00001  dbSNP: rs778482303

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463628	SCV000551993	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-08	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 421 of the PMS2 protein (p.Arg421Gln). This variant is present in population databases (rs778482303, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 411047). 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%. 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	RCV000580340	SCV000686113	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 421 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 individuals affected with breast cancer (PMID: 31780696, 33471991). This variant has been identified in 4/251060 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.
Ambry Genetics	RCV000580340	SCV001170865	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-19	criteria provided, single submitter	clinical testing	The p.R421Q variant (also known as c.1262G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1262. The arginine at codon 421 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual affected with breast cancer (Dutil J et al. Sci Rep, 2019 11;9:17769). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Division of Medical Genetics, University of Washington	RCV001257486	SCV001434296	uncertain significance	Lynch syndrome 4	2020-05-05	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an allele frequency of 0.00001593 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. PP3
GeneDx	RCV001753907	SCV002007309	uncertain significance	not provided	2021-08-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Dutil 2019); This variant is associated with the following publications: (PMID: 31780696)
Sema4, Sema4	RCV000580340	SCV002529779	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
Baylor Genetics	RCV001257486	SCV004207852	uncertain significance	Lynch syndrome 4	2023-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586719	SCV005076783	uncertain significance	not specified	2024-04-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1262G>A (p.Arg421Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251060 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1262G>A has been reported in the literature in individuals affected with breast cancer or gallbladder cancer without evidence of causality (e.g. Dutil_2019, Pandey_2020). These reports 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. ClinVar contains an entry for this variant (Variation ID: 411047). Based on the evidence outlined above, the variant was classified as uncertain significance.