Submissions for variant NM_000535.7(PMS2):c.1012C>G (p.Pro338Ala)

dbSNP: rs876660508

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219397	SCV000277996	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-29	criteria provided, single submitter	clinical testing	The p.P338A variant (also known as c.1012C>G), located in coding exon 10 of the PMS2 gene, results from a C to G substitution at nucleotide position 1012. The proline at codon 338 is replaced by alanine, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000480173	SCV000569509	uncertain significance	not provided	2022-11-14	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 22949387, 11574484, 28135145)
Invitae	RCV000541065	SCV000625495	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 338 of the PMS2 protein (p.Pro338Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 233592). 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 expected to disrupt PMS2 protein function with a positive 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	RCV000219397	SCV000904820	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 338 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). 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480173	SCV001470599	uncertain significance	not provided	2019-12-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798722	SCV002042779	uncertain significance	Breast and/or ovarian cancer	2021-04-23	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001249242	SCV001423179	not provided	Mismatch repair cancer syndrome 1		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 03-14-2019 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.