ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.610A>C (p.Asn204His)

dbSNP: rs746910555
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483433 SCV000565385 uncertain significance not provided 2015-02-27 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.610A>C at the cDNA level, p.Asn204His (N204H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has been reported in an individual with a personal and/or family history of breast and/or ovarian cancer (Castera 2014). PMS2 Asn204His 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 Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asn204His occurs at a position that is well conserved across vertebrates and is located in the ATPase domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Asn204His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000705642 SCV000834649 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-12-21 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. 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. ClinVar contains an entry for this variant (Variation ID: 418414). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 24549055). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 204 of the PMS2 protein (p.Asn204His).

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