Submissions for variant NM_000535.7(PMS2):c.20C>T (p.Ser7Leu)

dbSNP: rs587780048

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115672	SCV000149581	uncertain significance	not provided	2013-12-24	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.20C>T at the cDNA level, p.Ser7Leu (S7L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ser7Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a neutral polar amino acid is replaced with a neutral non-polar one, altering a position that is highly variable throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Ser7Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573096	SCV000670790	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.S7L variant (also known as c.20C>T), located in coding exon 1 of the PMS2 gene, results from a C to T substitution at nucleotide position 20. The serine at codon 7 is replaced by leucine, an amino acid with dissimilar 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 poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780641	SCV000918072	uncertain significance	not specified	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.20C>T (p.Ser7Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.20C>T has been reported in the literature (Mei_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000573096	SCV001349305	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 7 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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	RCV000115672	SCV001470048	uncertain significance	not provided	2020-02-21	criteria provided, single submitter	clinical testing
Invitae	RCV001854556	SCV002217767	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 7 of the PMS2 protein (p.Ser7Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs587780048, ExAC 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: 127772). 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.
Baylor Genetics	RCV003460823	SCV004205334	uncertain significance	Lynch syndrome 4	2023-10-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355531	SCV001550448	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ser7Leu variant was not identified in the literature. The variant was identified in dbSNP (ID: rs587780048) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx and Ambry Genetics). The variant was identified in control databases in 1 of 245412 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 1 of 30780 chromosomes (freq: 0.00003), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, European, Latino, or Other populations. The p.Ser7 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% 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.