ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2174+1G>A (rs267608172)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218995 SCV000272981 pathogenic Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Counsyl RCV000409361 SCV000488693 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000115677 SCV000149586 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2174+1G>A or IVS12+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 12 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Functional studies, including a splicing analysis using patient RNA and an in vitro minigene assay, have demonstrated aberrant splicing (van der Klift 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). PMS2 c.2174+1G>A has been reported in association with Lynch syndrome, and it has been observed in the compound heterozygous or homozygous state in individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome (Senter 2008, Vaughn 2010, Herkert 2011, Yurgelun 2017). Based on the current evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076844 SCV000697333 pathogenic Lynch syndrome 2018-05-21 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2174+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. RNA analysis was performed to study the effect of c.2174+1G>A on mRNA splicing and to confirm that this mutation is located in PMS2 and not in its highly homologous pseudogene PMS2CL. The variant allele was found at a frequency of 1.7e-05 in 239230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (1.7e-05 vs 0.00011), allowing no conclusion about variant significance. c.2174+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome and features of CMMRD. Specifically, the variant has been cited in multiple patients in both heterozygous, compound heterozygous (in trans with a second pathogenic PMS2 variant), and homozygous state, several of whom have loss of PMS2 via IHC. Carrying two MMR mutations in PMS2 in trans has been associated with constitutional mismatch repair-deficiency, which is characterized by colonic polyposis and hematologic, brain and gastrointestinal malignancies, as well as neurofribromas, which present at a young age and thus both mutations may be explaining the phenotype in the individuals reported. The variant alone was found in unaffected parents of probands, further supporting the idea that the variant is involved in constitutional mismatch repair-deficiency. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, but does not provide convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076844 SCV000108333 pathogenic Lynch syndrome 2014-03-14 reviewed by expert panel research Interrupts canonical donor splice site
Invitae RCV000539044 SCV000625591 pathogenic Hereditary nonpolyposis colon cancer 2018-12-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases (rs267608172, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been reported in the literature in individuals with colorectal cancer, and breast and ovarian cancer (PMID: 18602922, 28135145, 25186627, 26681312), and suspected Lynch syndrome (PMID: 26110232). In addition, this variant has been observed as homozygous in individuals with phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 20205264, 21376568, 23012243). ClinVar contains an entry for this variant (Variation ID: 91329). Experimental studies have shown that this splice change results in aberrant transcripts with skipping of exon 12 and/or insertions of about 300 and 600 bp in minigene assays and patient RNA (PMID: 21376568, 26247049), indicating that this nucleotide is crucial for normal RNA splicing. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000076844 SCV000271439 pathogenic Lynch syndrome 2016-03-04 criteria provided, single submitter clinical testing The c.2174+1G>A variant in PMS2 has been reported as heterozygous in 1 individua l, homozygous in 1 individual, and compound heterozygous with another disease-c ausing variant in 1 individual, all with PMS2-associated cancers (Senter 2008, Herkert 2011). It segregated in a compound heterozygous state with disease in on e affect sibling (Herkert 2011). It has also has been identified in 2/48882 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs267608172). However, this frequency is low enough to be cons istent with the frequency of Lynch syndrome in the general population. In vitro functional studies provide some evidence that the c.2174+1G>A variant may impact protein function (Van Der Klift, 2015). This variant occurs in the invariant re gion (+/- 1,2) of the splice consensus sequence and is predicted to cause altere d splicing leading to an abnormal or absent protein. Heterozygous loss of functi on of the PMS2 gene is an established disease mechanism in individuals with Lync h syndrome. In addition, it was classified as Pathogenic on April 16, 2014 by th e ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108333.3). In summary, th is variant meets our criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon predicted impact to the protein.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000115677 SCV000925691 not provided not provided no assertion provided in vitro

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