ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.825A>G (p.Gln275=) (rs876659736)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219153 SCV000276519 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-09 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Functionally-validated splicing mutation
GeneDx RCV000479060 SCV000568206 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.825A>G at the DNA level. Although this variant is silent at the coding level, preserving a Glutamine at codon 275, it is predicted to lead to the use of a cryptic, downstream splice acceptor site. Consistent with splicing models, multiple RNA analyses have demonstrated this variant to result in the use of a cryptic downstream splice acceptor site, resulting in the loss of 22 bases, which ultimately leads to a prematurely truncated transcript (Johannesma 2011, van der Klift 2015). In addition, this variant was observed in the compound heterozygous state in at least one individual with constitutional mismatch repair deficiency (Johannesma 2011). PMS2 c.825A>G was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, an adenine (A) at base 825, is not conserved. Based on the currently available information, we consider PMS2 c.825A>G to be a likely pathogenic variant.
Invitae RCV000541550 SCV000625697 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-03-06 criteria provided, single submitter clinical testing This sequence change affects codon 275 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in two individuals from the same family affected with symptoms consistent with constitutional mismatch repair deficiency (CMMR-D) (PMID: 21261604). This finding suggests that this variant contributes to disease. This variant has also been reported in individuals with suspected Lynch syndrome (PMID: 26110232, 28514183) and with breast cancer (PMID: 25856668). ClinVar contains an entry for this variant (Variation ID: 232390). Experimental studies using both patient-derived RNA and minigene assays have shown that this silent change results in a splicing defect and an aberrant transcript (PMID: 26247049). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763588 SCV000894427 likely pathogenic Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing

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