Submissions for variant NM_000535.7(PMS2):c.830C>T (p.Thr277Met)

dbSNP: rs1805322

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573847	SCV000670770	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-22	criteria provided, single submitter	clinical testing	The p.T277M variant (also known as c.830C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 830. The threonine at codon 277 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587439	SCV000697390	uncertain significance	not specified	2020-07-08	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.830C>T (p.Thr277Met) results in a non-conservative amino acid change located in the N-terminal (IPR002099) domain and S5 domain 2-like (IPR013507) domain of 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 2.8e-05 in 251422 control chromosomes (gnomAD). 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.830C>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000573847	SCV000904181	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 277 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). 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 been identified in 9/282828 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.
Invitae	RCV001049150	SCV001213184	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001553488	SCV001774368	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001553488	SCV002774696	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001071	SCV004839905	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 277 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). 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 been identified in 9/282828 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.