Submissions for variant NM_000179.3(MSH6):c.2417C>G (p.Ser806Cys)

gnomAD frequency: 0.00010  dbSNP: rs372990379

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160717	SCV000211351	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17531815, 21120944, 33471991, 28944238, 32885271, 32832836)
Counsyl	RCV000409643	SCV000488052	uncertain significance	Lynch syndrome 5	2015-12-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570608	SCV000669888	likely benign	Hereditary cancer-predisposing syndrome	2022-04-19	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.
Invitae	RCV000629702	SCV000750658	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160717	SCV000888256	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570608	SCV000903876	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 806 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28944238) and hereditary breast cancer (PMID: 32885271). In a large breast cancer case-control study, this variant has been observed in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 13/281900 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582637	SCV001821398	uncertain significance	not specified	2021-08-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2417C>G (p.Ser806Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250498 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4.8e-05 vs 0.00014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2417C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000570608	SCV002535737	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409643	SCV004018885	likely benign	Lynch syndrome 5	2023-03-28	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].
All of Us Research Program, National Institutes of Health	RCV003998511	SCV004840253	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 806 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28944238) and hereditary breast cancer (PMID: 32885271). In a large breast cancer case-control study, this variant has been observed in 7/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 13/281900 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354913	SCV001549641	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	MSH6, EXON4, c.2417C>G, p.Ser806Cys, Heterozygous, Uncertain SignificancernThe MSH6 p.Ser806Cys variant was not identified in the literature nor was it identified in the UMD-LSDB. The variant was identified in dbSNP (ID: rs372990379) as "With Uncertain Significance allele" and in ClinVar (5x as Uncertain Significance by GeneDx, Invitae, and 3 additional clinical laboratories). The variant was identified in control databases in 14 of 276194 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 11 of 24016 chromosomes (freq: 0.0005), Other in 1 of 6452 chromosomes (freq: 0.0002), and South Asian in 2 of 30778 chromosomes (freq: 0.00007), but not in the Latino, European Non-Finnish, Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser806 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.