rs200726484
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000535.7(PMS2):c.1309C>T(p.Pro437Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P437L) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1309C>T | p.Pro437Ser | missense_variant | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1309C>T | p.Pro437Ser | missense_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251250Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135840
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461792Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 727228
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 22, 2016 | Variant summary: The PMS2 c.1309C>T (p.Pro437Ser) variant causes a missense change involving a non-conserved nucleotide, which 4/5 in silico tools predict a benign. A functional study indicates that the variant of interest acted comparable to wild type MMR function. In addition, the variant of interest was reported to co-occur with another pathogenic PMS2 variant, c.1079_1080del, in an individual diagnosed with CrC at 43 y/o. LOVD - InSiGHT cites the variant in a male (adenocarc conlon transversum); AMS criteria negative; TUMOR_IHC: MLH1: positive; MSH2: positive; MSH6: positive; PMS2: negative; MLH1 Methylation: no methylation; Method: MS-MLPA; Indicates that the patient carried another pathogenic PMS2 variant c.1079_1080del (Classified as Class 5 by InSiGHT). Therefore, the patient described in LOVD is likely to be the same patient reported in the published reference. Furthermore, the IHC pattern supports the notion that the co-occuring PMS2 variant was the likely cause of colorectal cancer in this patient. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP). A clinical diagnostic laboratory cites the variant as "likely benign." Therefore, due to the reported co-occurrence, and comparable wild type MMR properties, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign." - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27435373, 21520333) - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 18, 2017 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at