Submissions for variant NM_000535.7(PMS2):c.913C>G (p.Leu305Val)

gnomAD frequency: 0.00001  dbSNP: rs750420143

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563069	SCV000663429	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-16	criteria provided, single submitter	clinical testing	The p.L305V variant (also known as c.913C>G), located in coding exon 9 of the PMS2 gene, results from a C to G substitution at nucleotide position 913. The leucine at codon 305 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000563069	SCV000686256	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 305 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: 26689913). This variant has been identified in 3/282544 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.
Invitae	RCV000630052	SCV000751008	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 305 of the PMS2 protein (p.Leu305Val). This variant is present in population databases (rs750420143, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 480299). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237930	SCV002010545	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563069	SCV002530402	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-13	criteria provided, single submitter	curation
Baylor Genetics	RCV003459300	SCV004205407	uncertain significance	Lynch syndrome 4	2023-10-06	criteria provided, single submitter	clinical testing