chr7-5989955-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000535.7(PMS2):āc.989A>Gā(p.Glu330Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000224 in 1,430,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E330Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.989A>G | p.Glu330Gly | missense_variant, splice_region_variant | 10/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.989A>G | p.Glu330Gly | missense_variant, splice_region_variant | 10/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 247842Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133998
GnomAD4 exome AF: 0.0000224 AC: 32AN: 1430096Hom.: 0 Cov.: 26 AF XY: 0.0000169 AC XY: 12AN XY: 712098
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with MSI-H colorectal cancer whose tumor demonstrated loss of MLH1 and PMS2 on immunohistochemistry (Wang et al., 2020); This variant is associated with the following publications: (PMID: 11574484, 31992580) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 31, 2023 | In the published literature, this variant has been reported in an individual with colorectal cancer, whose tumor exhibited microsatellite instability, and loss of MLH1 and PMS2 staining (PMID: 31615547 (2020)). The frequency of this variant in the general population, 0.000027 (3/112460 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2022 | The p.E330G variant (also known as c.989A>G) is located in coding exon 10 of the PMS2 gene. The glutamic acid at codon 330 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 10. This variant was identified in a proband diagnosed with MSI-H colorectal cancer at the age of 45 that showed loss of MLH1 and PMS2 staining on immunohistochemistry, but MLH1 promoter hypermethylation status was not available (Wang Q et al. J Med Genet, 2020 07;57:487-499). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 05, 2023 | This missense variant replaces glutamic acid with glycine at codon 330 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 an individual affected with early onset colorectal cancer, whose tumor displayed high microsatellite instability and loss of MLH1 and PMS2 protein via immunohistochemistry analysis (PMID: 31992580). MLH1 methylation status was not available for this tumor. This variant has been identified in 4/247842 chromosomes 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. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | This missense variant replaces glutamic acid with glycine at codon 330 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 an individual affected with early onset colorectal cancer, whose tumor displayed high microsatellite instability and loss of MLH1 and PMS2 protein via immunohistochemistry analysis (PMID: 31992580). MLH1 methylation status was not available for this tumor. This variant has been identified in 4/247842 chromosomes 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. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 330 of the PMS2 protein (p.Glu330Gly). This variant is present in population databases (rs761913816, gnomAD 0.003%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 31992580). ClinVar contains an entry for this variant (Variation ID: 567236). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 03, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at