Submissions for variant NM_000535.7(PMS2):c.2264T>C (p.Ile755Thr)

gnomAD frequency: 0.00002  dbSNP: rs386833410

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034625	SCV000565421	uncertain significance	not provided	2014-09-13	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2264T>C at the cDNA level, p.Ile755Thr (I755T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ile755Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile755Thr occurs at a position that is conserved across species and is located in the C-terminal nuclease domain (Fukui 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Ile755Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034625	SCV000697341	uncertain significance	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: The c.2264T>C variant affects a conserved nucleotide, resulting in amino acid change from Ile to Thr. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may create multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant has been reported in one patient with colon cancer (Carneiro da Silva_2015), but not found in 114882 control chromosomes. Because of the insufficient evidence and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics	RCV000708979	SCV000838168	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034625	SCV002009099	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257373	SCV002530279	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	curation
Ambry Genetics	RCV002257373	SCV002736584	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-20	criteria provided, single submitter	clinical testing	The p.I755T variant (also known as c.2264T>C), located in coding exon 13 of the PMS2 gene, results from a T to C substitution at nucleotide position 2264. The isoleucine at codon 755 is replaced by threonine, an amino acid with similar properties. This variant has been reported in a Brazilian individual who met Bethesda guidelines and was diagnosed at age 39 with colon cancer that demonstrated normal mismatch repair protein expression by immunohistochemistry (Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; de Angelis de Carvalho N et al. Cancers (Basel), 2020 Jul;12). This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108; Pinard A et al. Hum Mutat, 2016 12;37:1299-1307). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492333	SCV004239595	uncertain significance	Breast and/or ovarian cancer	2022-09-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002257373	SCV004359025	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 755 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 26437257). 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034625	SCV000043415	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034625	SCV001551520	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Ile755Thr variant was identified in 3 of 3098 proband chromosomes (frequency: 0.001) from individuals or families with Lynch syndrome (Carneiro da Silva 2015, Johnston 2012, Rossi 2017). The variant was also identified in dbSNP (ID: rs386833410) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx and three other submitters). The variant was identified in control databases in 3 of 244428 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 110452 chromosomes (freq: 0.00002), Finnish in 1 of 22160 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ile755 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a 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.