Submissions for variant NM_000535.7(PMS2):c.149G>A (p.Gly50Asp)

gnomAD frequency: 0.00002  dbSNP: rs539285592

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586511	SCV000211582	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with rectal cancer; however, tumor studies were discordant (Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 11574484, 27978560)
Invitae	RCV000542157	SCV000625530	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 50 of the PMS2 protein (p.Gly50Asp). This variant is present in population databases (rs539285592, gnomAD 0.003%). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 182805). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV000571665	SCV000670761	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-03	criteria provided, single submitter	clinical testing	The p.G50D variant (also known as c.149G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 149. The glycine at codon 50 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in 1/450 individuals diagnosed with colorectal cancer under age 50 and undergoing panel testing for 25 cancer susceptibility genes (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571665	SCV000686130	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 50 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset rectal cancer whose tumor was mismatch repair proficient (PMID: 27978560). This variant has been identified in 2/245762 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586511	SCV000697298	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.149G>A (p.Gly50Asp) variant located in the Histidine kinase-like ATPase, C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115490 (1/57745), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMS2 variant of 1/8802. In addition, one clinical diagnostic laboratories has classified this variant as "uncertain significance." The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.