Submissions for variant NM_000535.7(PMS2):c.1435C>G (p.His479Asp)

gnomAD frequency: 0.00002  dbSNP: rs376344586

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197213	SCV000254598	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 479 of the PMS2 protein (p.His479Asp). This variant is present in population databases (rs376344586, gnomAD 0.004%). 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: 216450). 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. 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.
Ambry Genetics	RCV000216807	SCV000277878	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-15	criteria provided, single submitter	clinical testing	The p.H479D variant (also known as c.1435C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1435. The histidine at codon 479 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is poorly 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	RCV000487350	SCV000569889	uncertain significance	not provided	2017-01-20	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1435C>G at the cDNA level, p.His479Asp (H479D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in the Exome Sequencing Project, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Histidine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 His479Asp occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Kondo 2001, Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 His479Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000216807	SCV000903881	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 479 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 4/251486 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.
Illumina Laboratory Services, Illumina	RCV001160657	SCV001322474	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192581	SCV001360810	uncertain significance	not specified	2019-05-02	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1435C>G (p.His479Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251486 control chromosomes (gnomAD). Although, this observation needs to be cautiously considered due to the technology used does not decipher between PMS2 and the pseudogene. 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.1435C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997027	SCV004844217	uncertain significance	Lynch syndrome	2023-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 479 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 4/251486 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.
True Health Diagnostics	RCV000216807	SCV000805282	likely benign	Hereditary cancer-predisposing syndrome	2018-05-09	no assertion criteria provided	clinical testing