ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2534A>T (p.His845Leu) (rs1554292741)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572695 SCV000663425 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-02 criteria provided, single submitter clinical testing Other data supporting pathogenic classification;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000629819 SCV000750775 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 845 of the PMS2 protein (p.His845Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with colorectal cancer (PMID: 25856668, 28135145). ClinVar contains an entry for this variant (Variation ID: 480297). 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 disruptive, 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.

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