Submissions for variant NM_000251.3(MSH2):c.10C>A (p.Gln4Lys)

gnomAD frequency: 0.00001  dbSNP: rs878853797

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227770	SCV000284091	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 4 of the MSH2 protein (p.Gln4Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 237357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000480195	SCV000565181	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.10C>A at the cDNA level, p.Gln4Lys (Q4K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln4Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln4Lys occurs at a position that is conserved across species and is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Gln4Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000563870	SCV000662219	likely benign	Hereditary cancer-predisposing syndrome	2023-02-15	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.
Color Diagnostics, LLC DBA Color Health	RCV000563870	SCV000684903	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 4 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 33471991). This variant has not been identified 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.
Sema4, Sema4	RCV000563870	SCV002528812	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465579	SCV002760628	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469135	SCV004193920	uncertain significance	Lynch syndrome 1	2023-10-26	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000563870	SCV004228036	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998750	SCV004826205	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 4 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 33471991). This variant has not been identified 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.