Submissions for variant NM_000535.7(PMS2):c.825A>T (p.Gln275His)

gnomAD frequency: 0.00001  dbSNP: rs876659736

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000708993	SCV000838190	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000987842	SCV001137314	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001046149	SCV001210038	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 275 of the PMS2 protein (p.Gln275His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal or breast cancer (PMID: 30256826, 35264596). ClinVar contains an entry for this variant (Variation ID: 584683). 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 with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV001188465	SCV001355533	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 275 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Variant histidine is a predominant reference amino acid in mammalian species, suggesting that this variant is likely tolerated for PMS2 function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 30256826 ). 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.
Ambry Genetics	RCV001188465	SCV002676165	likely benign	Hereditary cancer-predisposing syndrome	2020-06-10	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.
GeneDx	RCV003156288	SCV003845507	uncertain significance	not provided	2023-03-16	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; Observed in an individual with colorectal cancer (Martin-Morales et al., 2018); This variant is associated with the following publications: (PMID: 35264596, 11574484, 30256826)