Submissions for variant NM_000179.3(MSH6):c.854G>T (p.Ser285Ile)

gnomAD frequency: 0.00001  dbSNP: rs63750878

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212635	SCV000211264	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer or colon polyps (Kolodner et al., 1999; Tsai et al., 2019); Published functional studies are conflicting: does not affect nuclear transport of MSH6 nor ATP hydrolysis and is not resistant to DNA damaging agents, but does exhibit a decreased ability to bind ATP and alters subcellular localization (Cyr et al., 2008; Gassman et al., 2011; Belvederesi et al., 2012; Houlleberghs et al., 2017); This variant is associated with the following publications: (PMID: 23621914, 22851212, 28531214, 25637381, 10537275, 21437237, 18790734, 27899619, 26333163, 11900875, 30787465, 34445333, 30374176)
Ambry Genetics	RCV000160657	SCV000214780	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	The p.S285I variant (also known as c.854G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 854. The serine at codon 285 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was reported in the blood and tumor of an individual with a personal and family history colorectal cancer and was not detected in 199 controls (Kolodner RD et al. Cancer Res. 1999 Oct;59:5068-74). A functional study analyzed MSH6 missense alterations to determine their effect on biochemical activity of the MSH2-MSH6 heterodimer, this variant did not have a hydrolysis defect, suggesting that adenosine nucleotide processing is not disrupted (Cyr JL et al. J. Biol. Chem. 2008 Nov;283:31641-8). Another functional study determined that sub-cellular localization of the protein derived from this variant was comparable to wild-type, suggesting a proper MSH6 nuclear import (Belvederesi L et al. Fam. Cancer. 2012 Dec;11:675-80). However, another study reports that this variant showed a significant defect in nuclear localization as it is located within the general region of the nuclear localization signals, suggesting that cellular distribution may contribute to carcinogenesis (Gassman NR et al. PLoS ONE. 2011;6:e17907). This alteration was not found to affect mismatch repair function on an in-vitro assay measuring cells survival in response to DNA damaging agent 6-thioguanine exposure (Houlleberghs H et al. PLoS Genet. 2017 May;13:e1006765). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000556949	SCV000625012	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160657	SCV000690483	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 285 of the MSH6 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). Functional studies investigating ATP binding, ATPase activity, mismatch repair activity, and nuclear localization have provided inconsistent results (PMID: 18790734, 21437237, 22851212, 28531214). This variant has been reported in at least one individual affected with colorectal cancer (PMID: 10537275, 22851212), and an individual with unspecified cancer (PMID: 31391288). This variant has been identified in 2/251154 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	RCV001174593	SCV001337785	uncertain significance	not specified	2020-01-17	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.854G>T (p.Ser285Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251154 control chromosomes (gnomAD). c.854G>T has been reported in the literature in at least one individual affected with familial colorectal cancer (Kolodner_1999). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Several publications report experimental evidence evaluating an impact on protein function, with conflicting results. The variant protein demonstrated modestly reduced ATPase activity, but does not appear to to alter DNA binding or DNA mismatch repair (e.g. Cyr_2008, Houlleberghs_2017). Studies assessing an impact on nuclear localization are conflicting (e.g. Gassman_2011, Belvederesi_2012). Evaluation of CRC tumor tissue from a patient with the variant showed loss of heterozygosity of the wild-type allele, but only low levels of microsatellite instability (Kolodner_1999). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Sema4, Sema4	RCV000160657	SCV002536358	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997105	SCV004834812	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 285 of the MSH6 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). Functional studies investigating ATP binding, ATPase activity, mismatch repair activity, and nuclear localization have provided inconsistent results (PMID: 18790734, 21437237, 22851212, 28531214). This variant has been reported in at least one individual affected with colorectal cancer (PMID: 10537275, 22851212), and an individual with unspecified cancer (PMID: 31391288). This variant has been identified in 2/251154 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.
CSER _CC_NCGL, University of Washington	RCV000148648	SCV000190363	uncertain significance	Colorectal cancer	2014-06-01	no assertion criteria provided	research