ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1012C>G (p.Pro338Ala) (rs876660508)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219397 SCV000277996 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000480173 SCV000569509 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1012C>G at the cDNA level, p.Pro338Ala (P338A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Pro338Ala 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 Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Pro338Ala occurs at a position that is conserved across species and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Pro338Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000541065 SCV000625495 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-28 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 338 of the PMS2 protein (p.Pro338Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 233592). 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.
Color RCV000219397 SCV000904820 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-06 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV001249242 SCV001423179 not provided Turcot syndrome no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 03-14-2019 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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