ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.705+3A>G

gnomAD frequency: 0.00002  dbSNP: rs764334813
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000315777 SCV000469739 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000627726 SCV000551987 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-17 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764334813, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 360544). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown this variant is associated with multiple RNA products, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000579462 SCV000686229 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-10 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the +3 position of intron 6 of the PMS2 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 5/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000579462 SCV001188266 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-18 criteria provided, single submitter clinical testing The c.705+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 6 in the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago RCV001821094 SCV002065823 uncertain significance not specified 2021-05-03 criteria provided, single submitter clinical testing DNA sequence analysis of the PMS2 gene demonstrated a sequence change in intron 6, c.705+3A>G. This sequence change has been described in gnomAD with a frequency of 0.016% in the South Asian sub-population (dbSNP rs764334813). In silico splice prediction tools suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This change does not appear to have been previously described in patients with PMS2-related disorders. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354828 SCV001549538 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 c.705+3A>G variant was not identified in the literature nor was it identified in the COGR, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs764334813) as "With Uncertain significance allele", and in ClinVar database (classified as uncertain significance by Invitae and Color Genomics). The variant was identified in control databases in 5 of 246260 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 5 of 30782 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The c.705+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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