rs1057515572
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1731_1732delGCinsAGT(p.Arg578ValfsTer3) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000535.7 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1731_1732delGCinsAGT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from the deletion of two nucleotides and insertion of three nucleotides causing a translational frameshift with a predicted alternate stop codon (p.R578Vfs*3). This mutation, described as "c.1730_1731insA and c.1732C>T", was detected in trans with a second PMS2 mutation in two sisters with constitutional mismatch repair deficiency (CMMRD) (Auclair J et al. Hum. Mutat. 2007 Nov;28:1084-90). 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 variant creates a frameshift and premature translation stop signal in exon 11 of the PMS2 gene. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in trans with a pathogenic PMS2 missense variant in two siblings with clinical features consistent with constitutional mismatch repair deficiency (PMID: 17557300). 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. -
Lynch syndrome 4 Pathogenic:2
This 14 year old male has a history of intellectual disability, macrocephaly, overgrowth, and hyperinsulinemia. Genetic testing to date, including exome sequencing, has not yielded a diagnosis, but did identify a secondary finding. This variant was reported previously in a compound heterozygous state in siblings with early only cancer and a family history of colon cancer (Auclair, 2007). It is absent from gnomAD. It is expected to cause a frameshift resulting in a premature stop codon. There is no reported paternal family history of cancer. -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Carcinoma of colon Pathogenic:1
The PMS2 p.Arg578Valfs*3 variant was identified in the literature in two sisters: one with severe unexplained anemia, oligodendroglioma, two synchronous colon adenocarcinomas, and a poorly differentiated adenomatous polyp; and the other with brain angioma, colon cancer, multiple dysplastic adenomatous polyps, and endometrial cancer (Auclair 2007). This variant co-occurred with the pathogenic PMS2 variant c.137G>T (p.Ser46Ile, Auclair 2007); these sisters were likely affected with Biallelic Mismatch Repair Deficiency syndrome. The variant was also identified in dbSNP (ID: rs1057515572) as "With Pathogenic allele" and ClinVar (classified as pathogenic by GeneDx and OMIM; and as likely pathogenic by one submitter). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1731_1732delinsAGT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 578 and leads to a premature stop codon at position 580. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.1731_1732delinsAGT (p.Arg578ValfsX3) 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. The variant is a multinucleotide change resulting from c.1730dupA and c.1732C>T. The variant was absent in 251352 control chromosomes. c.1731_1732delinsAGT has been reported in the literature in individuals affected with Lynch Syndrome associated cancers (example: Auclair_2007). Four 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. -
Mismatch repair cancer syndrome 4 Pathogenic:1
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not provided Pathogenic:1
Frameshift 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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Tian et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20531397, 22585707, 18709565, 21376568, 31054147, 17557300) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at