ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.917T>C (p.Val306Ala) (rs786201878)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164381 SCV000215016 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000588443 SCV000279297 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.917T>C at the cDNA level, p.Val306Ala (V306A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant has been reported in an individual with endometrial cancer who also harbored a pathogenic BRCA2 variant (Ring 2016). PMS2 Val306Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. PMS2 Val306Ala is located in the ATPase domain (Guarne 2001). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Val306Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000470824 SCV000551971 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-10 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 306 of the PMS2 protein (p.Val306Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer, endometrial cancer and colorectal adenomas (PMID: 27443514, 25938944, 25186627). ClinVar contains an entry for this variant (Variation ID: 185028). 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.
Integrated Genetics/Laboratory Corporation of America RCV000588443 SCV000697399 uncertain significance not provided 2016-04-01 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.917T>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Ala. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was not found in 119904 control chromosomes. It has been cited in one patient that had polyps and a first degree relative with CRC or polyposis, but co-segregation was not determined (Weren_NG_2015). In addition, one clinical laboratory classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000213750 SCV000731463 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing The p.Val306Ala variant in PMS2 has been reported in 1 individual with endometri al cancer (Ring 2016), and has also been reported in ClinVar (Variation ID 18502 8). This variant was absent from large population studies. Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val306 Ala variant is uncertain.
Counsyl RCV000662825 SCV000785670 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-10-26 criteria provided, single submitter clinical testing
Mendelics RCV000708990 SCV000838186 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000164381 SCV000909665 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-24 criteria provided, single submitter clinical testing

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