Submissions for variant NM_000535.7(PMS2):c.1243G>T (p.Val415Leu)

dbSNP: rs138387687

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000465085	SCV000552056	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 415 of the PMS2 protein (p.Val415Leu). This variant is present in population databases (rs138387687, gnomAD 0.007%). ClinVar contains an entry for this variant (Variation ID: 411079). 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. 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	RCV000587977	SCV000565396	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Reported in one individual with breast cancer, specific phenotype information not provided (Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587977	SCV000697290	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.1243G>T (p.Val415Leu) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/120354 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. 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.
Color Diagnostics, LLC DBA Color Health	RCV000772619	SCV000905804	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 415 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. In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251130 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.
Ambry Genetics	RCV000772619	SCV001170724	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.V415L variant (also known as c.1243G>T), located in coding exon 11 of the PMS2 gene, results from a G to T substitution at nucleotide position 1243. The valine at codon 415 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not 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.
Sema4, Sema4	RCV000772619	SCV002529777	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268088	SCV002550725	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001883	SCV004839823	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 415 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. In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251130 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.