ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1103A>G (p.Asn368Ser) (rs777814445)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205079 SCV000259374 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 368 of the PMS2 protein (p.Asn368Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs777814445, ExAC 0.01%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 219486). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000479052 SCV000565395 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1103A>G at the cDNA level, p.Asn368Ser (N368S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asn368Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. PMS2 Asn368Ser occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Asn368Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000584467 SCV000690996 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000584467 SCV001178385 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing Insufficient evidence

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