Submissions for variant NM_000535.7(PMS2):c.212A>G (p.Asn71Ser)

dbSNP: rs587780049

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759919	SCV000149584	uncertain significance	not provided	2019-08-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000558750	SCV000625582	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 71 of the PMS2 protein (p.Asn71Ser). This variant is not present in population databases (gnomAD no frequency). 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: 127774). 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 expected to disrupt PMS2 protein function with a positive 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759919	SCV000889622	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014552	SCV001175273	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-29	criteria provided, single submitter	clinical testing	The p.N71S variant (also known as c.212A>G), located in coding exon 3 of the PMS2 gene, results from an A to G substitution at nucleotide position 212. The asparagine at codon 71 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly 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	RCV001824611	SCV002074465	uncertain significance	not specified	2022-01-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467053	SCV004207845	uncertain significance	Lynch syndrome 4	2023-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001014552	SCV004359705	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 71 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported 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.