Submissions for variant NM_000535.7(PMS2):c.779_780inv (p.Ser260Trp)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213103	SCV000276615	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-23	criteria provided, single submitter	clinical testing	The c.779_780delCCinsGG variant (also known as p.S260W), located in coding exon 7 of the PMS2 gene, results from a C to G substitution at nucleotide positions 779 and 780. The serine at codon 260 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001036558	SCV001199928	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-30	criteria provided, single submitter	clinical testing	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. This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 260 of the PMS2 protein (p.Ser260Trp). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. 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: 232473). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.
Color Diagnostics, LLC DBA Color Health	RCV000213103	SCV001352373	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan at codon 260 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401146	SCV004122679	uncertain significance	not specified	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.779_780delinsGG (p.Ser260Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like (IPR013507) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 281520 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.779_780delinsGG in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.