Submissions for variant NM_000535.7(PMS2):c.113C>T (p.Ala38Val)

gnomAD frequency: 0.00002  dbSNP: rs148270248

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167349	SCV000218201	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	The p.A38V variant (also known as c.113C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 113. The alanine at codon 38 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000229343	SCV000285045	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 38 of the PMS2 protein (p.Ala38Val). This variant is present in population databases (rs148270248, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This missense change has been observed to co-occur in individuals with a different variant in PMS2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 187605). 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	RCV000167349	SCV000686095	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 38 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 been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759911	SCV000889606	uncertain significance	not provided	2019-01-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000987853	SCV001137332	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000759911	SCV001797260	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, glioma, papillary thyroid cancer, and pituitary adenoma (Lu et al., 2015; Cetani et al., 2019; Mio et al., 2021; Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 26689913, 31486992, 33821390, 35402282, 11574484, 36243179)
Fulgent Genetics, Fulgent Genetics	RCV002478518	SCV002784078	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-08-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150031	SCV003838400	uncertain significance	Breast and/or ovarian cancer	2021-12-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000987853	SCV004205395	uncertain significance	Lynch syndrome 4	2023-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995585	SCV004842160	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 38 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 been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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.