chr7-5987503-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000535.7(PMS2):c.1262G>A(p.Arg421Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421L) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1262G>A | p.Arg421Gln | missense_variant | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1262G>A | p.Arg421Gln | missense_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251060Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135762
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461862Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727226
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2023 | This missense variant replaces arginine with glutamine at codon 421 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31780696, 33471991). This variant has been identified in 4/251060 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2024 | The p.R421Q variant (also known as c.1262G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1262. The arginine at codon 421 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual affected with breast cancer (Dutil J et al. Sci Rep, 2019 11;9:17769). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 13, 2022 | - - |
Lynch syndrome 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | May 05, 2020 | To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an allele frequency of 0.00001593 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 08, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Dutil 2019); This variant is associated with the following publications: (PMID: 31780696) - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 421 of the PMS2 protein (p.Arg421Gln). This variant is present in population databases (rs778482303, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 411047). 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 expected to disrupt PMS2 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at