7-5987504-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1261C>T(p.Arg421*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,056 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 (★★★). 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 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461860Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:3
Coding sequence variation resulting in a stop codon -
The p.Arg421X variant in PMS2 has been reported in one carrier with unspecified phenotype (Suerink 2015), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 421, which is p redicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summ ary, this variant meets our criteria to be classified as pathogenic for Lynch sy ndrome in an autosomal dominant manner based upon the predicted impact to the pr otein. -
This variant changes 1 nucleotide in exon 11/15 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 individuals suspected of having Lynch syndrome (PMID: 23012243, 26110232). This variant has not been identified 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. -
not provided Pathogenic:3
Observed in individuals with suspected Lynch Syndrome (PMID: 23012243, 26110232, 31992580); 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 31159747, 24728327, 26110232, 23012243, 31589614, 30787465, 31992580, 33259954, 33693762, 35988656) -
PP4, PVS1 -
This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000066 (1/152196 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 31300551 (2020), 31159747 (2019), 29345684 (2018)), and Lynch syndrome (PMID: 26110232 (2016), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:3
This variant changes 1 nucleotide in exon 11 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 not been identified 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.R421* pathogenic mutation (also known as c.1261C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1261. This changes the amino acid from an arginine to a stop codon within coding exon 11. This pathogenic alteration was present in 1/130 European families with PMS2 mutations meeting either Bethesda criteria or "MSI-testing-indicated-by-a-pathologist" criteria (Suerink M et al. Genet. Med. 2016 Apr;18:405-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
This is a point mutation replacing one nucleotide in the position 1261 of the PMS2 gene, leading in the replacement of Arginine with a termination stop codon in the position 421 of the PMS2 protein. The resulting protein is truncated and non functional. This particular variant has been described in international literature in families with colorectal cancer and/or Lynch syndrome (PMID: 23012243, PMID: 26110232). The mutation database ClinVar contains an entry for this variant (Variation ID: 91299). -
Lynch syndrome 4 Pathogenic:3
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.1261C>T (p.Arg421X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251060 control chromosomes. c.1261C>T has been reported in the literature in individuals with suspected Hereditary Nonpolyposis Colorectal Cancer (e.g. Vaughn_2013, Suerink_2016). It has also been reported by different studies in a number of individuals affected with breast cancer (e.g. Roberts_2018, Tsaousis_2019, Fostira_2020), with one of the studies concluding that pathogenic variants in the PMS2 gene are associated with an increased risk for breast cancer following retrospective review of patient data (Roberts_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23012243, 29345684, 26110232, 31159747, 31300551). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely 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.Arg421*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or suspected Lynch syndrome (PMID: 23012243, 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: 91299). For these reasons, this variant has been classified as Pathogenic. -
Endometrial carcinoma Pathogenic:1
The p.ARG421X variant was identified as a nonsense mutation in the paper by Topp (2014). The variant was also identified in COSMIC in large intestine tissue and InSiGHT Colon Cancer databases. In ClinVar the variant was classified as pathogenic by InSiGHT. This residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) have not provided predictions regarding the impact to the protein. In summary, based on the above information this variant meets our laboratory's criteria to be classified as pathogenic. -
not specified Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at