Submissions for variant NM_000535.7(PMS2):c.1344A>T (p.Gly448=) (rs759192470)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164596	SCV000215255	likely benign	Hereditary cancer-predisposing syndrome	2014-12-09	criteria provided, single submitter	clinical testing
Color	RCV000164596	SCV000911287	likely benign	Hereditary cancer-predisposing syndrome	2017-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000442013	SCV000517396	likely benign	not specified	2016-12-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America	RCV000442013	SCV000920043	uncertain significance	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1344A>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246256 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1344A>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, with one laboratory classifying the variant as uncertain significance and the other as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae	RCV000229726	SCV000285065	uncertain significance	Hereditary nonpolyposis colon cancer	2018-11-21	criteria provided, single submitter	clinical testing	This sequence change affects codon 448 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. This variant is present in population databases (rs759192470, ExAC 0.001%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 185217). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare silent change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.