Submissions for variant NM_000535.7(PMS2):c.1576G>A (p.Asp526Asn)

dbSNP: rs63750686

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217885	SCV000277406	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-15	criteria provided, single submitter	clinical testing	The p.D526N variant (also known as c.1576G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1576. The aspartic acid at codon 526 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is 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.
GeneDx	RCV000480867	SCV000565413	uncertain significance	not provided	2023-07-31	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17016615)
Color Diagnostics, LLC DBA Color Health	RCV000217885	SCV000686141	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 526 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 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.
Invitae	RCV000630090	SCV000751046	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765956	SCV000897377	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271472	SCV002555673	uncertain significance	not specified	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1576G>A (p.Asp526Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251074 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.1576G>A in individuals affected with Lynch Syndrome or PMS2-associated cancers and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998027	SCV004844179	uncertain significance	Lynch syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 526 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 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.