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

gnomAD frequency: 0.00003  dbSNP: rs767904893

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168211	SCV000218876	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-07	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). 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	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: 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	2023-10-30	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 supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11292842, 32547938)