Submissions for variant NM_000535.7(PMS2):c.1048C>T (p.Leu350Phe)

gnomAD frequency: 0.00002  dbSNP: rs587782875

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132505	SCV000187601	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-25	criteria provided, single submitter	clinical testing	The p.L350F variant (also known as c.1048C>T), located in coding exon 10 of the PMS2 gene, results from a C to T substitution at nucleotide position 1048. The leucine at codon 350 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV002228671	SCV000551930	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 350 of the PMS2 protein (p.Leu350Phe). This variant is not present in population databases (gnomAD no frequency). 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: 142991). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health	RCV000132505	SCV000909661	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 350 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985900	SCV001134573	uncertain significance	not provided	2019-06-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462048	SCV004205348	uncertain significance	Lynch syndrome 4	2023-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998149	SCV004839856	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 350 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354637	SCV001549301	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Leu350Phe variant was not identified in the literature. The variant was also identified in dbSNP (ID: rs587782875) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae and Ambry Genetics). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Leu350 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.