Submissions for variant NM_000251.3(MSH2):c.2717T>C (p.Ile906Thr)

gnomAD frequency: 0.00002  dbSNP: rs587780687

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122988	SCV000166277	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000412095	SCV000488246	uncertain significance	Lynch syndrome 1	2016-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573859	SCV000662235	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	The p.I906T variant (also known as c.2717T>C), located in coding exon 16 of the MSH2 gene, results from a T to C substitution at nucleotide position 2717. The isoleucine at codon 906 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved and threonine is a reference amino acid in several species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573859	SCV000690091	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 906 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/31384 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.
Mendelics	RCV000412095	SCV001135764	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001558333	SCV001780257	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949387, 27720647, 18822302, 21120944, 27873144, 9774676, 25085752)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001558333	SCV002046494	uncertain significance	not provided	2020-12-10	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251992	SCV002523021	uncertain significance	See cases	2022-01-24	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, BP4
Myriad Genetics, Inc.	RCV000412095	SCV004018318	likely benign	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV004542928	SCV004782730	uncertain significance	MSH2-related disorder	2023-10-26	criteria provided, single submitter	clinical testing	The MSH2 c.2717T>C variant is predicted to result in the amino acid substitution p.Ile906Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47710000-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997408	SCV004829886	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 906 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/31384 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.