ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.964G>A (p.Val322Ile)

gnomAD frequency: 0.00002  dbSNP: rs587782208
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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 RCV000130884 SCV000185792 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-20 criteria provided, single submitter clinical testing The p.V322I variant (also known as c.964G>A), located in coding exon 9 of the PMS2 gene, results from a G to A substitution at nucleotide position 964. The valine at codon 322 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in a cohort of 1781 individuals referred for commercial BRCA1/2 gene testing (Tung N et al. Cancer. 2015 Jan;121:25-33). 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.
GeneDx RCV000212861 SCV000211599 uncertain significance not provided 2022-08-03 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 26333163, 25186627, 11574484)
Counsyl RCV000411983 SCV000488569 uncertain significance Lynch syndrome 4 2016-04-28 criteria provided, single submitter clinical testing
Invitae RCV000467383 SCV000551982 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 322 of the PMS2 protein (p.Val322Ile). This variant is present in population databases (rs587782208, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 142066). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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 Diagnostics, LLC DBA Color Health RCV000130884 SCV000909663 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-02 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 322 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 2/251258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781751 SCV000920041 uncertain significance not specified 2017-09-18 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.964G>A (p.Val322Ile) variant located in the Ribosomal protein S5 domain 2-type fold (via InterPro) involves the alteration of a conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 2/246084 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, the technology utilized for this dataset do not rule out pseudogene interference and thus this data needs to be cautiously considered. A publication, Tung_2015, reports the variant to have been found in one BrC pt, however, limited information is provided (ie, lack of cosegregation data). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000781751 SCV002047124 uncertain significance not specified 2021-05-17 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000411983 SCV004019815 uncertain significance Lynch syndrome 4 2023-04-04 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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