Submissions for variant NM_000251.3(MSH2):c.1347G>C (p.Lys449Asn)

gnomAD frequency: 0.00001  dbSNP: rs587781331

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129078	SCV000183781	likely benign	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210120	SCV000266190	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000524342	SCV000284106	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000482497	SCV000565190	uncertain significance	not provided	2018-05-02	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1347G>C at the cDNA level, p.Lys449Asn (K449N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has been reported in at least two patients who had a personal history of ovarian and other cancers (Tung 2015, Shirts 2016). MSH2 Lys449Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in within the Lever domain and in the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Lys449Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129078	SCV000684931	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 449 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). 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 been reported in an individual affected with breast and ovarian cancer (PMID: 25186627), and in an individual affected with ovarian and thyroid cancer (PMID: 26845104). This variant has been identified in 1/250800 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.
Counsyl	RCV000662718	SCV000785472	uncertain significance	Lynch syndrome 1	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781551	SCV000919685	uncertain significance	not specified	2017-11-03	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1347G>C (p.Lys449Asn) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/245736 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). This variant has been reported in multiple affected individuals without strong evidence for or against causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Myriad Genetics, Inc.	RCV000662718	SCV004018305	uncertain significance	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000210120	SCV004824993	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 449 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). 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 been reported in an individual affected with breast and ovarian cancer (PMID: 25186627), and in an individual affected with ovarian and thyroid cancer (PMID: 26845104). This variant has been identified in 1/250800 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.