Submissions for variant NM_000535.7(PMS2):c.1901A>G (p.His634Arg)

gnomAD frequency: 0.00003  dbSNP: rs767904893

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168211	SCV000218876	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 634 of the PMS2 protein (p.His634Arg). This variant is present in population databases (rs767904893, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 32547938). ClinVar contains an entry for this variant (Variation ID: 188248). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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	RCV000220002	SCV000278045	likely benign	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000220002	SCV000909645	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 634 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, who also carried a pathogenic variant in BRCA1 (PMID: 32547938). This variant has been identified in 7/251410 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.
Sema4, Sema4	RCV000220002	SCV002530240	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
GeneDx	RCV003318558	SCV004022808	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Observed in a patient with breast cancer; however, this individual also harbored a pathogenic variant in BRCA1 (PMID: 32547938); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11292842, 32547938)
All of Us Research Program, National Institutes of Health	RCV003995612	SCV004844123	uncertain significance	Lynch syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 634 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, who also carried a pathogenic variant in BRCA1 (PMID: 32547938). This variant has been identified in 7/251410 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003318558	SCV005625891	uncertain significance	not provided	2024-11-29	criteria provided, single submitter	clinical testing	The PMS2 c.1901A>G (p.His634Arg) variant has been reported in the published literature in an individual with breast cancer; this individual was also positive for a BRCA1 frameshift variant (PMID: 32547938 (2020)). The frequency of this variant in the general population, 0.0002 (7/34582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003318558	SCV005877540	uncertain significance	not provided	2024-06-04	criteria provided, single submitter	clinical testing	The PMS2 c.1901A>G; p.His634Arg variant (rs767904893, ClinVar Variation ID: 188248) is reported in the literature in an individual affected with breast cancer, this individual also carried a pathogenic variant in BRCA1 (Nikitin 2020). This variant is found in the Admixed American population with an allele frequency of 0.02% (7/34,582 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.019). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Nikitin AG et al. Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants. Front Oncol. 2020 May 29;10:666. PMID: 32547938.