Submissions for variant NM_000179.3(MSH6):c.1844G>C (p.Cys615Ser)

gnomAD frequency: 0.00005  dbSNP: rs730881793

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212653	SCV000211284	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23047549, 25186627, 26580448, 25085752, 17531815, 21120944)
Vantari Genetics	RCV000160673	SCV000267055	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410091	SCV000430964	uncertain significance	Lynch syndrome 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000410091	SCV000488356	uncertain significance	Lynch syndrome 5	2016-03-03	criteria provided, single submitter	clinical testing
Invitae	RCV000524120	SCV000551194	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000160673	SCV000580202	likely benign	Hereditary cancer-predisposing syndrome	2018-06-21	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.
Mendelics	RCV000304378	SCV000837889	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160673	SCV000903259	likely benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193697	SCV001362730	uncertain significance	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1844G>C (p.Cys615Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250636 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (4.8e-05 vs 0.00014), allowing no conclusion about variant significance. c.1844G>C has been reported in the literature in individuals affected with epithelial ovarian cancer (Pal_2012), breast cancer (Tung_2014), pediatric cancer (Zhang_2015), and unspecified cancer (Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31391288, 23047549, 25186627, 26580448). 14 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments, ranging from predominantly uncertain significance to benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798554	SCV002042036	uncertain significance	Breast and/or ovarian cancer	2021-05-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212653	SCV002046947	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), breast cancer (PMID: 25186627 (2015)), and leukemia (PMID: 26580448 (2015)). It is also reported in at least one individual suspected of having Lynch syndrome (PMID: 36793599 (2023)). The frequency of this variant in the general population, 0.00023 (8/35422 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV001193697	SCV002067736	uncertain significance	not specified	2018-12-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160673	SCV002535665	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193697	SCV002552298	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410091	SCV004019016	likely benign	Lynch syndrome 5	2023-03-29	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].