Submissions for variant NM_000535.7(PMS2):c.903G>T (p.Lys301Asn)

dbSNP: rs267608153

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076896	SCV000108392	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	G>non-G at last base of exon with 6 bases of the intron not GTRRGT (splicing aberration has not been quantified)
Ambry Genetics	RCV000215563	SCV000277457	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	clinical testing	The c.903G>T pathogenic mutation (also known as p.K301N), located in coding exon 8 of the PMS2 gene, results from a G to T substitution at nucleotide position 903. The lysine at codon 301 is replaced by asparagine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in multiple individuals with personal and/or family histories consistent with Lynch syndrome (Goodenberger ML et al. Genet. Med., 2016 Jan;18:13-9; Suerink M et al. Genet. Med., 2016 Apr;18:405-9; ten Broeke SW et al. J. Clin. Oncol., 2015 Feb;33:319-25; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885) and several had isolated loss of PMS2 staining on immunohistochemistry in their Lynch-associated tumors (Senter L et al. Gastroenterology. 2008 August;135(2):419-28; Tomsic J et al. Clin. Genet. 2013 Mar; 83(3):238-43; van der Klift HM et al. Mol. Genet. Genomic Med 2015 Jul; 3(4):327-45). RNA studies have demonstrated that this alteration results in skipping of coding exon 8 (Ambry internal data; van der Klift HM et al. Mol. Genet. Genomic Med 2015 Jul; 3(4):327-45). One French individual diagnosed with constitutional mismatch repair deficiency syndrome (CMMRD) was found to carry the c.903G>T mutation in conjunction with another PMS2 pathogenic mutation (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000255696	SCV000322156	pathogenic	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing predicted to cause protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Suerink et al., 2016; van der Klift et al., 2015; van der Klift et al., 2016); Observed in multiple individuals with personal or family histories of Lynch syndrome-associated cancers, many who had tumors that exhibited high microsatellite instability and/or abnormal PMS2 protein expression on immunohistochemistry (Senter et al., 2008; Goodenberger et al., 2016; Suerink et al., 2016; Martin-Morales et al., 2018; Wang et al., 2020); Observed in a patient with constitutional mismatch repair deficiency syndrome (CMMRD) in published literature, however a second pathogenic variant was not noted (Lavoine et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 32549215, 29922827, 28888541, 22577899, 18602922, 25512458, 26110232, 26269718, 25345868, 11574484, 26247049, 32571878, 30256826, 30787465, 31332305, 27435373, 31992580, 26318770)
Illumina Laboratory Services, Illumina	RCV000778110	SCV000469736	likely pathogenic	Lynch syndrome 4	2016-09-28	criteria provided, single submitter	clinical testing	The PMS2 c.903G>T (p.Lys301Asn) missense variant has been reported in a heterozygous state in three unrelated individuals affected with a Lynch syndrome-associated tumor and showing isolated loss of PMS2 by immunohistochemistry (Senter et al. 2008). In addition, Suerink et al. (2016) reported three heterozygous carriers of the p.Lys301Asn variant from one family, wherein at least one individual was affected. The p.Lys301Asn variant was absent from 80 controls (Tomsic et al. 2013) and is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium, though this is based on only one allele in a region of good sequencing coverage. Functional studies used RT-PCR analyses of patient RNA as well as minigene assays to demonstrate that the p.Lys301Asn variant caused an out of frame skipping of exon 8 (van der Klift et al. 2015). Based on the evidence, the p.Lys301Asn variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000524483	SCV000552010	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	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 301 of the PMS2 protein (p.Lys301Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs267608153, gnomAD 0.003%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency (CMMR-D) syndrome and Lynch syndrome-related cancers (PMID: 18602922, 25856668, 26110232, 26318770, 27435373; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91377). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000215563	SCV000906858	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This variant causes a G>T nucleotide substitution at the end of exon 8 in the PMS2 gene. Splice site prediction tools predicted RNA splicing impact at the intron 8 splice donor site. Functional RNA studies reported the variant transcript has complete skipping of exon 8 (r.804_903del and p.Tyr268*) as detected by RT-PCR on patient-derived RNA and corroborated in RNA assays (PMID: 26247049, 27435373, 31332305). This variant has been reported in multiple individuals with personal or family history of Lynch syndrome-associated cancer (PMID: 18602922, 25512458, 25856668, 26110232, 30256826), including tumor samples that showed microsatellite instability and loss of DNA mismatch repair protein (InSiGHT). This variant has also been reported in an individual diagnosed with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 26318770). This variant has been identified in 1/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
MGZ Medical Genetics Center	RCV000778110	SCV002580849	likely pathogenic	Lynch syndrome 4	2022-02-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255696	SCV002774371	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	The PMS2 c.903G>T (p.Lys301Asn) variant is located at the last nucleotide of exon 8, and experimental studies have shown this variant causes skipping of exon 8, resulting in a frameshift and premature termination of PMS2 protein synthesis or absent mRNA expression (PMIDs: 26247049 (2015), 26110232 (2016)). In addition, the variant has been reported in individuals/families with Lynch syndrome-associated cancers (PMIDs: 27435373 (2016), 26110232 (2016), 25512458 (2015), 22577899 (2013), 18602922 (2008)). It has also been reported in an individual with CMMRD (PMID: 26318770 (2015)). The frequency of this variant in the general population, 0.000029 (1/34578 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000255696	SCV003826083	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000778110	SCV004187600	likely pathogenic	Lynch syndrome 4	2023-09-19	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 26247049, 27435373].
Baylor Genetics	RCV000778110	SCV004205386	pathogenic	Lynch syndrome 4	2023-10-15	criteria provided, single submitter	clinical testing
GeneReviews	RCV001804828	SCV002054090	not provided	Lynch syndrome 1		no assertion provided	literature only