ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.961G>A (p.Val321Ile) (rs377043696)

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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 RCV000130331 SCV000185181 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing The p.V321I variant (also known as c.961G>A), located in coding exon 9 of the PMS2 gene, results from a G to A substitution at nucleotide position 961. The valine at codon 321 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown pathogenicity in one individual from a cohort of 145 unrelated patient samples submitted for PMS2 whole gene analysis. Additionally, authors note that this individual's tumor exhibited isolated loss of PMS2 expression by immunohistochemistry (IHC) (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). The alteration was also detected in the germline of a 54-year-old male diagnosed with two ascending colorectal cancers; both tumors exhibited isolated loss of PMS2 by IHC and high microsatellite instability (MSI-H). This individual did not meet Amsterdam II criteria (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20). This amino acid position is well 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 this alteration remains unclear.
Invitae RCV000206806 SCV000260552 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 321 of the PMS2 protein (p.Val321Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs377043696, ExAC 0.05%). This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 20205264, 25871621). ClinVar contains an entry for this variant (Variation ID: 141713). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000222996 SCV000279291 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.961G>A at the cDNA level, p.Val321Ile (V321I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has been identified in at least two individuals with cancer whose tumors showed isolated loss of PMS2 protein expression by immunohistochemistry (Vaughn 2010, Dudley 2015). PMS2 Val321Ile was observed at an allele frequency of 0.02% (5/25,664) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val321Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000130331 SCV000902933 likely benign Hereditary cancer-predisposing syndrome 2015-12-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193814 SCV001362948 uncertain significance not specified 2019-03-13 criteria provided, single submitter clinical testing Variant summary: PMS2 c.961G>A (p.Val321Ile) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain and DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277022 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (4e-05 vs 0.00011), allowing no conclusion about variant significance. Of note, this observance needs to be cautiously considered due to the region indicated to be affected by pseudogene interference. c.961G>A has been reported in the literature in affected individuals whose tumors exhibited isolated loss of PMS2 expression by immunohistochemistry (Dudley_2015, Vaughn_2010). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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