Submissions for variant NM_000535.7(PMS2):c.1169C>T (p.Ala390Val)

gnomAD frequency: 0.00006  dbSNP: rs587780039

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212859	SCV000149560	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with endometrial cancer in conjunction with multiple other variants in hereditary cancer genes (Castellanos et al., 2017); This variant is associated with the following publications: (PMID: 28051113, 32566746, 31386297)
Ambry Genetics	RCV000115651	SCV000184320	likely benign	Hereditary cancer-predisposing syndrome	2019-04-30	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.
Invitae	RCV000229947	SCV000285048	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 390 of the PMS2 protein (p.Ala390Val). This variant is present in population databases (rs587780039, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28051113, 31386297). ClinVar contains an entry for this variant (Variation ID: 127754). 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	RCV000115651	SCV000904176	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 390 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 endometrial cancer (PMID: 28051113) and in an individual affected with an unspecified cancer (PMID: 31386297). This variant has been identified in 8/278308 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030722	SCV001193690	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199850	SCV001370575	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1169C>T (p.Ala390Val) 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 2.4e-05 in 246938 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1169C>T has been reported in the literature in at least one individual affected with Lynch Syndrome (e.g. Castellanos_2017) and other cancer phenotypes (Kiyozumi_2019, Salvati_2022, Hu_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: six submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212859	SCV001469601	uncertain significance	not provided	2019-11-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421993	SCV004106357	uncertain significance	PMS2-related condition	2023-03-21	criteria provided, single submitter	clinical testing	The PMS2 c.1169C>T variant is predicted to result in the amino acid substitution p.Ala390Val. This variant was reported with uncertain significance in an individual with Lynch syndrome (Supplemental Table 1, Kiyozumi et al. 2019. PubMed ID: 31386297). This variant was also reported, along with variants in other cancer related genes, in an individual with endometrial cancer with a family history of breast, colon, endometrial, and gastric cancers (Sample_R1, Castellanos et al. 2017. PubMed ID: 28051113). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6027227-G-A) and has conflicting interpretations in ClinVar ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127754/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467050	SCV004205425	uncertain significance	Lynch syndrome 4	2023-09-28	criteria provided, single submitter	clinical testing