rs199700509
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000535.7(PMS2):c.1828A>G(p.Lys610Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K610Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1828A>G | p.Lys610Glu | missense_variant | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1828A>G | p.Lys610Glu | missense_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251458Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727228
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74474
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 22, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 15, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2023 | The p.K610E variant (also known as c.1828A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1828. The lysine at codon 610 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in a lung cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun, 2015 Dec;6:10086). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with lung cancer (Lu et al., 2015); This variant is associated with the following publications: (PMID: 26689913) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | PMS2: PM2, BP4 - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 610 of the PMS2 protein (p.Lys610Glu). This variant is present in population databases (rs199700509, gnomAD 0.005%). This missense change has been observed in individual(s) with lung cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 188287). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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 | Oct 10, 2023 | - - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at