Submissions for variant NM_000251.3(MSH2):c.1681G>A (p.Glu561Lys)

gnomAD frequency: 0.00002  dbSNP: rs63750328

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524354	SCV000284120	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000410128	SCV000487855	uncertain significance	Lynch syndrome 1	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000484663	SCV000567206	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1681G>A at the cDNA level, p.Glu561Lys (E561K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in at least one individual with a personal and/or family history suspicious for Lynch syndrome, and an RT-PCR assay using this individual's RNA did not reveal any defect in splicing (Auclair 2006). MSH2 Glu561Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Glu561Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568086	SCV000669724	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	The p.E561K variant (also known as c.1681G>A), located in coding exon 11 of the MSH2 gene, results from a G to A substitution at nucleotide position 1681. The glutamic acid at codon 561 is replaced by lysine, an amino acid with similar properties. This variant was detected in an HNPCC family and did not cause any detectable effect on normal splicing (Auclair J et al. Hum Mutat, 2006 Feb;27:145-54). This alteration has been reported as variant of uncertain significance in 2/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000568086	SCV000690015	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 561 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). The variant has a neutral effect on MSH2 function in a methylation tolerance assay (PMID: 30998989), and does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). An RNA study has also shown that the variant had no aberrant splicing (PMID:16395668). This variant has been reported in a family affected with Lynch Syndrome (PMID:16395668). In a large breast cancer case-control study, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 4/250114 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.
GeneKor MSA	RCV000568086	SCV000822046	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198848	SCV001369843	uncertain significance	Mismatch repair cancer syndrome 1	2018-10-05	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1.
Division of Medical Genetics, University of Washington	RCV000410128	SCV001424806	uncertain significance	Lynch syndrome 1	2019-06-27	criteria provided, single submitter	clinical testing	The c.1681G>A variant has been reported in the literature in an individual from a family with Lynch syndrome (Auclair 2006). The c.1681G>A variant has an overall allele frequency of 0.000016 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484663	SCV002046199	uncertain significance	not provided	2020-10-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568086	SCV002534395	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410128	SCV004018391	likely benign	Lynch syndrome 1	2023-03-22	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].
Baylor Genetics	RCV000410128	SCV004196177	uncertain significance	Lynch syndrome 1	2023-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997152	SCV004834081	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 561 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). The variant has a neutral effect on MSH2 function in a methylation tolerance assay (PMID: 30998989), and does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). An RNA study has also shown that the variant had no aberrant splicing (PMID:16395668). This variant has been reported in a family affected with Lynch Syndrome (PMID:16395668). In a large breast cancer case-control study, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 4/250114 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.