Submissions for variant NM_000535.7(PMS2):c.353G>A (p.Ser118Asn)

dbSNP: rs1394474494

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629959	SCV000750915	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change affects codon 118 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with clinical features consistent with Lynch syndrome (PMID: 31992580; Invitae). ClinVar contains an entry for this variant (Variation ID: 525724). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV002457987	SCV002617279	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-29	criteria provided, single submitter	clinical testing	The c.353G>A pathogenic mutation (also known as p.S118N), located in coding exon 4 of the PMS2 gene, results from a G to A substitution at nucleotide position 353. This change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In addition to the splicing impact, this alteration changes the serine residue to an asparagine residue at codon 118, an amino acid with highly similar properties. This variant has been identified in individuals whose Lynch syndrome-associated tumors demonstrated isolated loss of PMS2 staining on immunohistochemistry (Wang Q et al. J Med Genet, 2020 07;57:487-499; Ambry internal data). In one study, coding exon 4 skipping was reported for this variant upon PMS2 transcript analysis using RNA isolated from patient samples (Wang Q et al. J Med Genet, 2020 07;57:487-499). Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. 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). In addition, the missense alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451495	SCV004187631	likely pathogenic	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358610	SCV001554396	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Ser118Asn variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in the LOVD Human Mismatch Repair Gene Database (1 entry, pathogenicity unknown). The variant was identified in control databases in 1 of 230230 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 107116 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ser118Asn residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Ser118Asn variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001692240	SCV001906127	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001692240	SCV001954567	pathogenic	not provided		no assertion criteria provided	clinical testing