rs587780062
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.823C>T(p.Gln275*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q275Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000535.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251410Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460578Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726680
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Lynch syndrome 4 Pathogenic:6
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This c.823C>T (p.Gln275*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with cancer (PMID: 22848017, 25512458, 24689082, 26681312). The c.823C>T (p.Gln275*) variant in the PMS2 gene is classified as pathogenic. -
ACMG codes:PVS1; PS4M; PM2; PP5 -
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
The PMS2 c.823C>T (p.Gln275Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with Lynch-syndrome associated cancers (PMID: 27435373, 31992580). This variant has also been reported in conjunction with another pathogenic variant in an individual with constitutional mismatch repair deficiency (PMID: 22848017). This variant has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -
not provided Pathogenic:5
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium; This variant is associated with the following publications: (PMID: 24689082, 26681312, 28514183, 26110232, 23012243, 25512458, 31992580, 31447099, 30787465, 33087929, 22848017) -
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This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251410 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 31992580 (2020), 25512458 (2015), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -
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Lynch syndrome Pathogenic:2
The c.823C>T (p.Gln275*) variant in the PMS2 gene is located on the exon 8 and introduces a premature translation termination codon (p.Gln275*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer or constitutional mismatch repair-deficiency syndrome (PMID: 28514183, 24689082, 27435373, 26110232, 23012243, 22848017). Loss-of-function variants in PMS2 are known to be pathogenic and variants located downstream to this position in this exon have been reported as pathogenic (PMID: 28514183, 25512458, 35223509, p.Gln288fs, ClinVar ID: 91376). The variant is reported in ClinVar (ID: 127796). The variant is rare in the general population according to gnomAD (2/251410). Therefore, the c.823C>T (p.Gln275*) variant of PMS2 has been classified as pathogenic. -
The p.Gln275X variant in PMS2 has been reported in at least 4 heterozygous individuals with PMS2-associated cancers and in 1 compound heterozygous individual with constitutive mismatch repair deficiency (Espenschied 2017, Susswein 2016, Suerink 2016, Hansen 2014, Vaughn 2013, Yeung 2013). This variant has been identified in 2/34590 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (pathogenic by several clinical labs (ClinVar ID 127796). This nonsense variant leads to a premature termination codon at position 275, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 8 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with constitutional mismatch mismatch repair deficiency who also carried another pathogenic PMS2 variant in trans (PMID: 22848017), as well as in multiple individuals affected with Lynch syndrome (PMID: 25512458, 27435373, 31992580). This variant has been identified in 2/251410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The p.Q275* pathogenic mutation (also known as c.823C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 823. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in two Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome families in the Netherlands (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33(4):319-25); in a child diagnosed with constitutional mismatch repair deficiency (CMMR-D) who also had a second PMS2 mutation (Yeung JT et al. Pediatr Blood Cancer. 2013 Jan;60(1):137-9); and in a patient with endometrial cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
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Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.823C>T (p.Gln275X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251410 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Yeung_2013, Hansen_2014, ten Broeke_2015, van der Klift_2016, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln275*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs587780062, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, and constitutional mismatch repair deficiency (PMID: 23012243, 24689082, 26110232). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 127796). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at