ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.903G>T (p.Lys301Asn) (rs267608153)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215563 SCV000277457 pathogenic Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
Color RCV000215563 SCV000906858 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000255696 SCV000322156 likely pathogenic not provided 2016-03-25 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.903G>T at the cDNA level, p.Lys301Asn (K301N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAT). This variant was observed in multiple individuals with personal or family histories of Lynch syndrome-associated cancers, many who had tumors that exhibited abnormal PMS2 protein expression on immunohistochemistry (Senter 2008, Goodenberger 2015, Suerink 2015, Ten Broeke 2015). This variant was observed to cause aberrant splicing in a minigene assay, leading to skipping of exon 8, and has been reported to result in a loss of RNA expression (Suerink 2015, van der Klift 2015). However, the data from the RNA analysis was not provided for review in these studies. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014). PMS2 Lys301Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Lys301Asn occurs at a position that is conserved across species and is located in the ATPase domain (Fukui 2011, Guarne 2001). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict this variant to cause the loss of the natural splice donor site and lead to abnormal splicing. Based on the currently available information, we consider PMS2 Lys301Asn to be a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778110 SCV000469736 likely pathogenic Hereditary nonpolyposis colorectal cancer type 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.
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)
Invitae RCV000524483 SCV000552010 pathogenic Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 301 of the PMS2 protein (p.Lys301Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 8 of the PMS2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs267608153, ExAC 0.009%). This variant has been observed in several individuals and families affected with Lynch syndrome-related cancers (PMID: 18602922, 26110232, 25856668, 27435373). Also, it has been reported in individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 26318770, Invitae). In one of them, the variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in PMS2 (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 91377). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change results in skipping of exon 8 during mRNA splicing (PMID: 26247049). For these reasons, this variant has been classified as Pathogenic.

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