ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1113T>G (p.Asn371Lys) (rs989130272)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479971 SCV000567505 uncertain significance not provided 2016-11-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1113T>G at the cDNA level, p.Asn371Lys (N371K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asn371Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asn371Lys occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant may create or enhance a cryptic splice donor site upstream of the natural splice donor site, which could possibly lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether PMS2 Asn371Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000794983 SCV000934421 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 371 of the PMS2 protein (p.Asn371Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 419598). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV001017366 SCV001178440 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-13 criteria provided, single submitter clinical testing Insufficient evidence

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