Submissions for variant NM_000535.7(PMS2):c.5A>G (p.Glu2Gly)

gnomAD frequency: 0.00001  dbSNP: rs876658233

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219403	SCV000273193	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-04	criteria provided, single submitter	clinical testing	The p.E2G variant (also known as c.5A>G), located in coding exon 1 of the PMS2 gene, results from an A to G substitution at nucleotide position 5. The glutamic acid at codon 2 is replaced by glycine, an amino acid with similar properties. This variant was observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557539	SCV000625670	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001559433	SCV001781656	uncertain significance	not provided	2021-03-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Lerner-Ellis 2020); This variant is associated with the following publications: (PMID: 31784482)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001559433	SCV004219015	uncertain significance	not provided	2023-09-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491965	SCV004239600	uncertain significance	Breast and/or ovarian cancer	2022-09-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357598	SCV001553111	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Glu2Gly variant was not identified in the literature nor was it identified in the COGR, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs876658233) as "With Uncertain significance allele ", and in ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 1 of 245330 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 110950 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu2 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.