ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1399G>A (p.Val467Ile) (rs373611083)

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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 RCV000131574 SCV000186580 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-23 criteria provided, single submitter clinical testing The p.V467I variant (also known as c.1399G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1399. The valine at codon 467 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000457616 SCV000551955 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 467 of the PMS2 protein (p.Val467Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs373611083, ExAC 0.03%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 142447). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000656947 SCV000565403 uncertain significance not provided 2020-05-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485817 SCV000601817 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131574 SCV000903129 likely benign Hereditary cancer-predisposing syndrome 2015-11-25 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249988 SCV001424002 uncertain significance Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656947 SCV001551003 uncertain significance not provided no assertion criteria provided clinical testing The PMS2 p.Val332Ile variant was not identified in the literature nor was it identified in COGR, MutDB, LOVD 3.0, Insight Colon Cancer Gene Variant Database or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs373611083), ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics, and as likely benign by Color), and Cosmic (prostate, endometrium, large intestine and upper aerodigestive tract carcinomas). The variant was identified in control databases in 15 of 282874 chromosomes at a frequency of 0.00005303 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 5 of 24964 chromosomes (freq: 0.0002), East Asian in 3 of 19948 chromosomes (freq: 0.00015) and European (non-Finnish) in 7 of 129184 chromosomes (freq: 0.000054), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Val332 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a 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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