Submissions for variant NM_000535.7(PMS2):c.1092T>A (p.Asp364Glu)

gnomAD frequency: 0.00001  dbSNP: rs370066853

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217971	SCV000275268	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-10	criteria provided, single submitter	clinical testing	The p.D364E variant (also known as c.1092T>A), located in coding exon 10 of the PMS2 gene, results from a T to A substitution at nucleotide position 1092. The aspartic acid at codon 364 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well 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.
Invitae	RCV000475489	SCV000551943	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 364 of the PMS2 protein (p.Asp364Glu). This variant is present in population databases (rs370066853, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419; Invitae). ClinVar contains an entry for this variant (Variation ID: 231423). 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 with a negative predictive value of 80%. 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.
GeneDx	RCV000484259	SCV000565394	uncertain significance	not provided	2023-02-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individual(s) with breast cancer (Tung et al., 2016); This variant is associated with the following publications: (PMID: 30267214, 11574484, 26976419)
Color Diagnostics, LLC DBA Color Health	RCV000217971	SCV000903600	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 364 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 been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/282586 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491977	SCV004239578	uncertain significance	Breast and/or ovarian cancer	2022-08-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488474	SCV004240817	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1092T>A (p.Asp364Glu) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like (IPR013507) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251196 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1092T>A has been reported in the literature in individuals affected with breast cancer or colorectal cancer (Tung_2016, Poliani_2022). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 26976419, 36356413). Four 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.