rs372297364
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS1_Supporting
The NM_001322011.2(PMS2):c.-339C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000304 in 1,613,616 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001322011.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152008Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251492Hom.: 1 AF XY: 0.0000294 AC XY: 4AN XY: 135918
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461608Hom.: 1 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 727120
GnomAD4 genome AF: 0.000118 AC: 18AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74258
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
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The p.R199C variant (also known as c.595C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 595. The arginine at codon 199 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in 1/1260 individuals with a history of Lynch syndrome-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This missense variant replaces arginine with cysteine at codon 199 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 9/282888 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. -
not provided Uncertain:3
The PMS2 c.595C>T (p.Arg199Cys) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 25186627 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)), and suspected Lynch syndrome (PMID: 25980754 (2015)). This variant was also observed in reportedly healthy individuals (PMID: 36243179 (2022)).The frequency of this variant in the general population, 0.00016 (5/30616 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer or a Lynch syndrome-associated cancer and/or polyps (PMID: 33471991, 25186627, 25980754); This variant is associated with the following publications: (PMID: 29570743, 25980754, 25589618, 25186627, 29887214, 33471991, 11574484, 36243179) -
Lynch syndrome 4 Uncertain:3
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
The PMS2 c.595C>T (p.Arg199Cys) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 including 1 homozygote (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Lynch syndrome Uncertain:2
PMS2 NM_000535.5:c.595C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -
This missense variant replaces arginine with cysteine at codon 199 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 9/282888 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. -
not specified Uncertain:1
Variant summary: PMS2 c.595C>T (p.Arg199Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251492 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. c.595C>T, has been reported in the literature in individuals affected with Lynch Syndrome (Tung_2015, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25186627). ClinVar contains an entry for this variant (Variation ID: 187514). Based on the evidence outlined above, the variant was classified as uncertain significance. -
PMS2-related disorder Uncertain:1
The PMS2 c.595C>T variant is predicted to result in the amino acid substitution p.Arg199Cys. This variant has been reported in a cohort of individuals with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, supplemental table 2), and individuals with breast cancer (Tung et al. 2015. PubMed ID: 25186627, supplemental table; reported as chr7_6038849_G_A in supplementary tables, Breast Cancer Association et al. 2021. PubMed ID: 33471991). However, its pathogenicity was not determined with further studies (e.g. segregation, functional assays). This variant has a subpopulation frequency of up to 0.016% in the gnomAD database, including one homozygote and it is reported as likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187514/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at