ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.430A>G (p.Ile144Val)

dbSNP: rs876659055
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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 RCV000216714 SCV000275050 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-18 criteria provided, single submitter clinical testing The p.I144V variant (also known as c.430A>G), located in coding exon 5 of the PMS2 gene, results from an A to G substitution at nucleotide position 430. The isoleucine at codon 144 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000 alleles tested) in our clinical cohort. 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 p.I144V remains unclear.
Invitae RCV000799111 SCV000938760 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-01-26 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 231257). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 144 of the PMS2 protein (p.Ile144Val).

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