Submissions for variant NM_000535.7(PMS2):c.2412G>C (p.Lys804Asn)

gnomAD frequency: 0.00001  dbSNP: rs547715146

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131772	SCV000186818	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	The p.K804N variant (also known as c.2412G>C), located in coding exon 14 of the PMS2 gene, results from a G to C substitution at nucleotide position 2412. The lysine at codon 804 is replaced by asparagine, an amino acid with similar properties. This amino acid position is poorly 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.
GeneDx	RCV000222535	SCV000279152	uncertain significance	not provided	2016-03-14	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2412G>C at the cDNA level, p.Lys804Asn (K804N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Lys804Asn was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed at significant allele frequency in 1000 Genomes. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Lys804Asn occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located within the nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Lys804Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000689497	SCV000817151	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 804 of the PMS2 protein (p.Lys804Asn). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 142572). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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	RCV001193254	SCV001361982	uncertain significance	not specified	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2412G>C (p.Lys804Asn) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 221484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2412G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467186	SCV004205368	uncertain significance	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131772	SCV004358992	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 804 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 not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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.