rs587779328
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000535.7(PMS2):c.1463C>T(p.Ala488Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,938 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. A488G) 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.1463C>T | p.Ala488Val | missense_variant | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1463C>T | p.Ala488Val | missense_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461834Hom.: 0 Cov.: 43 AF XY: 0.0000138 AC XY: 10AN XY: 727212
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74294
ClinVar
Submissions by phenotype
Lynch syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 12, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 23, 2023 | This missense variant replaces alanine with valine at codon 488 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). TA functional study reported that this variant did not impair DNA mismatch repair activity in vitro (PMID: 27435373). This variant has been detected in a suspected Lynch syndrome family (PMID: 27435373). This variant has been identified in 2/251460 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 cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2023 | This missense variant replaces alanine with valine at codon 488 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported that this variant did not impair DNA mismatch repair activity in vitro (PMID: 27435373). This variant has been detected in a suspected Lynch syndrome family (PMID: 27435373). This variant has been identified in 2/251460 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 12, 2019 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with adenomatous colorectal polyps, but demonstrated proficient mismatch repair (MMR) activity in an in vitro MMR assay (van der Klift et al., 2016); This variant is associated with the following publications: (PMID: 26333163, 27435373) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 488 of the PMS2 protein (p.Ala488Val). This variant is present in population databases (rs587779328, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary cancer (PMID: 27435373). ClinVar contains an entry for this variant (Variation ID: 91303). 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%. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 27435373). 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 30, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at