Submissions for variant NM_000535.7(PMS2):c.917T>A (p.Val306Glu)

dbSNP: rs786201878

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232471	SCV000285163	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 306 of the PMS2 protein (p.Val306Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 31019026, 34645491). ClinVar contains an entry for this variant (Variation ID: 237933). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PMS2 function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV000565783	SCV000676174	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.V306E variant (also known as c.917T>A), located in coding exon 9 of the PMS2 gene, results from a T to A substitution at nucleotide position 917. The valine at codon 306 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853300	SCV000996143	likely pathogenic	Lynch syndrome 4	2018-05-04	criteria provided, single submitter	clinical testing	This variant has not been previously published in the literature to our knowledge, but has been previously reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/237933/). The Val306Glu variant was not observed in large population cohorts and is absent from the ExAC and gnomAD population databases, thus it is presumed to be rare. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect and this variant is located in the ATPase domain. This variant has been observed in the homozygous state in an individual with a clinical history suggestive of a congenital mismatch repair deficiency (CMMR-D) at an independent commercial genetic testing laboratory. Based on the available evidence, the Val306Glu variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174830	SCV001338196	uncertain significance	not specified	2020-02-27	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.917T>A (p.Val306Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.917T>A in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284035	SCV001469607	uncertain significance	not provided	2020-03-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000853300	SCV005056401	uncertain significance	Lynch syndrome 4	2024-03-10	criteria provided, single submitter	clinical testing