Submissions for variant NM_000535.7(PMS2):c.903G>A (p.Lys301=)

dbSNP: rs267608153

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228489	SCV000285162	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change affects codon 301 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs267608153, gnomAD 0.002%). This variant has been observed in individual(s) with Lynch-related cancers (internal data). ClinVar contains an entry for this variant (Variation ID: 237932). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, and produces a non-functional protein and/or introduces a premature termination codon (internal data). This variant disrupts the c.903G nucleotide in the PMS2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18602922, 26110232). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000573516	SCV000676178	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	The c.903G>A pathogenic mutation (also known as p.K301K), located in coding exon 8 of the PMS2 gene, results from a G to A substitution at nucleotide position 903. This nucleotide substitution does not change the lysine at codon 301. 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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). Another alteration impacting the same donor site (c.903G>T) has been shown to have a similar impact on splicing in multiple patients whose Lynch syndrome-associated tumors demonstrated isolated loss of PMS2 on IHC (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; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614513	SCV000731660	likely pathogenic	Lynch syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The c.903G>T (p.Lys301Lys) variant in PMS2 has been identified in at least 2 individuals with PMS2_associated cancers (Matejcic 2020 PMID: 32832836) and has also been reported by other clinical laboratories in ClinVar (Variation ID 237932). This variant has also been identified in 0.003% (3/113600) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this silent variant does not alter an amino acid residue, it is located in the last base of the exon, which is part of the 5’ splice region. Computational tools suggest an impact to splicing. A different variant at the same nucleotide position (c.903G>T, p.Lys301Asn) has been reported in individuals with Lynch syndrome (Senter 2008 PMID: 18602922, Lavoine 2015 PMID: 26318770, Suerink 2015 PMID: 26110232). Additionally, in vitro functional splicing studies have shown that the c.903G>T change causes aberrant splicing that leads to skipping of exon 8 and results in a premature stop codon (van der Klift 2015 PMID: 26247049), suggesting that variants at this position are likely to disrupt RNA splicing. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PP3, PM5_Supporting, PS3_Moderate.
GeneDx	RCV001762520	SCV002008686	likely pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	Variant at the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal history of prostate cancer in published literature (Matejcic 2020); This variant is associated with the following publications: (PMID: 31447099, 32832836)
Myriad Genetics, Inc.	RCV003454708	SCV004187626	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 [Myriad internal data].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238758	SCV005888202	likely pathogenic	Hereditary nonpolyposis colon cancer	2025-01-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.903G>A (p.Lys301Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. RNA analysis indicated that this variant results in skipping of exon 8 and introduces a premature termination codon (LabCorp Genetics (formerly Invitae), internal data). The variant allele was found at a frequency of 1.2e-05 in 251238 control chromosomes (gnomAD). c.903G>A has been reported in the literature in individuals affected with colonic- and extracolonic tumors that belong to the Lynch Syndrome spectrum (e.g. Adar_2018, Matejcic_2020). These data indicate that the variant may be associated with disease. In addition, a different variant affecting the same nucleotide (c.903G>T) is reported in patients (HGMD), and is classified as Likely pathogenic by multiple labs in ClinVar (Variation ID 91377), citing experimental studies for splice-effect. The following publications have been ascertained in the context of this evaluation (PMID: 29750335, 32832836). ClinVar contains an entry for this variant (Variation ID: 237932). Based on the evidence outlined above, the variant was classified as likely pathogenic.