Submissions for variant NM_000179.3(MSH6):c.2408A>G (p.Asp803Gly)

gnomAD frequency: 0.00004  dbSNP: rs63751450

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130124	SCV000184956	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-01	criteria provided, single submitter	clinical testing	The p.D803G variant (also known as c.2408A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2408. The aspartic acid at codon 803 is replaced by glycine, an amino acid with similar properties. This variant was first reported in a familial CRC kindred and has been shown to reduce the ATP-binding potential of MSH6 (Kolodner RD et al. Cancer Res. 1999 Oct;59:5068-74; Cyr JL and Heinen CD. J. Biol. Chem. 2008 Nov;283:31641-8). This alteration was also identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000586083	SCV000211297	uncertain significance	not provided	2024-03-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal and other cancers (PMID: 10537275, 25479140, 26689913, 25186627, 28944238, 31428572); This variant is associated with the following publications: (PMID: 22788692, 22290698, 25637381, 10537275, 23621914, 19766128, 27363283, 26689913, 11900875, 25479140, 25186627, 26206375, 28944238, 31391288, 34445333, 33471991, 24393486, 31428572, 17531815, 21120944, 36922933, 18790734)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524143	SCV000261326	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000410826	SCV000488182	uncertain significance	Lynch syndrome 5	2016-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130124	SCV000537593	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 803 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). A functional study has reported that this variant protein has reduced nucleotide exchange and ATPase activities (PMID: 18790734). This variant has been reported in individuals affected with colorectal, breast, pancreatic cancer or glioblastoma multiforme (PMID: 10537275, 25186627, 25479140, 26689913, 31391288, 31428572, 33471991), as well as in several healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 22/282092 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212666	SCV000539712	uncertain significance	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified as VUS by expert panel in 2013; no new evidence supporting pathogenicity since then
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212666	SCV000695812	likely benign	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2408A>G (p.Asp803Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 1614502 control chromosomes, predominantly at a frequency of 0.00035 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2408A>G has been reported in the literature in cohorts of individuals affected with various cancers such as the Ontario Pancreas cancer study cohort, the TGCA cohort, breast and colorectal cancer (example, Grant_2015, Kolodner_1999, Tung_2015, Lu_2015, Zhunssova_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. A recent study testing MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios to compute a tumor characteristic likelihood ratio (TCLR) included this variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information resulted in its classification as likely benign (Li_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect affect the ability to be cross linked to ATP, suggesting the mutant appears to uncouple the mismatch binding and ATP hydrolysis activities of the MSH2-MSH6 heterodimer (Cyr_2008). However, the in-vivo implications of this finding are unclear. The following publications have been ascertained in the context of this evaluation (PMID: 10537275, 18790734, 22290698, 23621914, 11900875, 25479140, 25186627, 26689913, 19766128, 31428572, 31391288). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=9) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586083	SCV000888255	uncertain significance	not provided	2018-04-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000410826	SCV001135819	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130124	SCV002535734	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410826	SCV004018972	benign	Lynch syndrome 5	2024-06-26	criteria provided, single submitter	clinical testing	This variant is considered 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: 27363726]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Baylor Genetics	RCV003466944	SCV004197649	uncertain significance	Endometrial carcinoma	2024-03-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997077	SCV004834332	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 803 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). A functional study has reported that this variant protein has reduced nucleotide exchange and ATPase activities (PMID: 18790734). This variant has been reported in individuals affected with colorectal, breast, pancreatic cancer or glioblastoma multiforme (PMID: 10537275, 25186627, 25479140, 26689913, 31391288, 31428572, 33471991), as well as in several healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 22/282092 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	RCV000148651	SCV000190366	uncertain significance	Colorectal cancer	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356592	SCV001551804	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Asp803Gly variant was identified in 4 of 13218 proband chromosomes (frequency: 0.0003) from individuals or families with pancreatic cancer, colorectal or breast cancer, and glioblastoma (Grant 2015, Kolodner 1999, Lu 2015, Tung 2015). The variant was also identified in dbSNP (ID: rs63751450) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight, Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics, and four clinical laboratories), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (2x as uncertain). The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 23 of 276376 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6458 chromosomes (freq: 0.0002), European in 4 of 125932 chromosomes (freq: 0.00003), Ashkenazi Jewish in 9 of 10136 chromosomes (freq: 0.0009), and South Asian in 9 of 30782 chromosomes (freq: 0.0003), but not in the African, Latino, East Asian, or Finnish populations. The p.Asp803 residue is 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.