Submissions for variant NM_000535.7(PMS2):c.20C>G (p.Ser7Trp)

dbSNP: rs587780048

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219730	SCV000278549	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.S7W variant (also known as c.20C>G), located in coding exon 1 of the PMS2 gene, results from a C to G substitution at nucleotide position 20. The serine at codon 7 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is poorly 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	RCV000219730	SCV000686175	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/250298 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	RCV000806920	SCV000946942	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine with tryptophan at codon 7 of the PMS2 protein (p.Ser7Trp). The serine residue is weakly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is present in population databases (rs587780048, ExAC 0.006%). 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: 234058). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
All of Us Research Program, National Institutes of Health	RCV003998596	SCV004842184	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan 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 been identified in 1/250298 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.