ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.-7T>C (rs199660792)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129024 SCV000172926 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-07 criteria provided, single submitter clinical testing The c.-7T>C variant is located in the 5' untranslated region (5’ UTR) of the PMS2 gene. This variant results from a T to C substitution 7 bases upstream from the first translated codon. This variant was previously reported in the SNPDatabase as rs199660792. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.01% (1/13,006) total alleles studied and 0.01% (1/8600) European American alleles.<span style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 23,0100 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of c.-7T>C remains unclear.
GeneDx RCV000254679 SCV000211597 likely benign not specified 2017-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000293218 SCV000469750 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254679 SCV000601861 likely benign not specified 2016-11-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254679 SCV000697388 likely benign not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: PMS2 c.-7T>C is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 276226 control chromosomes, predominantly at a frequency of 0.0036 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 32 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. Sequence alignment suggests the sequence in this region does not have high homology to the sequences from pseudogenes (sequence identify<90%). c.-7T>C has been reported in the literature in individuals affected with colon cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in literature (MSH2 c.1906G>C, p.A636P), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely benign, 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000129024 SCV000910618 likely benign Hereditary cancer-predisposing syndrome 2015-04-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356694 SCV001551933 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 c.-7T>C variant was not identified in the literature nor was it identified in the COGR, Cosmic, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors, databases. The variant was identified in dbSNP (ID: rs199660792) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics and two clinical laboratories; as likely benign by GeneDx and one clinical laboratory). The variant was identified in control databases in 43 of 276226 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 1 of 34410 chromosomes (freq: 0.00003), European in 3 of 125914 chromosomes (freq: 0.00002), Ashkenazi Jewish in 36 of 10134 chromosomes (freq: 0.004), Finnish in 1 of 25788 chromosomes (freq: 0.00004), while the variant was not observed in the African, East Asian, and South Asian populations. The c.-7T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The -7 position is within the Kozak consensus sequence however it is a position that is known to vary without consequence. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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