chr7-5978607-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000535.7(PMS2):āc.2264T>Cā(p.Ile755Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 150,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000199 AC: 3AN: 150456Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249476Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134862
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000689 AC: 10AN: 1452372Hom.: 0 Cov.: 31 AF XY: 0.00000830 AC XY: 6AN XY: 722456
GnomAD4 genome AF: 0.0000199 AC: 3AN: 150456Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1AN XY: 73408
ClinVar
Submissions by phenotype
not provided Uncertain:5
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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. -
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. -
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. -
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Hereditary cancer-predisposing syndrome Uncertain:3
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. -
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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. -
Breast and/or ovarian cancer Uncertain:1
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Lynch syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at