Submissions for variant NM_000179.3(MSH6):c.650A>G (p.Asp217Gly)

gnomAD frequency: 0.00013  dbSNP: rs554012110

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131354	SCV000186329	likely benign	Hereditary cancer-predisposing syndrome	2020-07-20	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.
GeneDx	RCV000212632	SCV000211258	likely benign	not provided	2021-02-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23047549, 28944238)
Invitae	RCV000167904	SCV000218552	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000411184	SCV000489127	uncertain significance	Lynch syndrome 5	2016-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131354	SCV000685512	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 217 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 observed in individuals affected with ovarian cancer (PMID: 23047549), colorectal cancer (PMID: 28944238), melanoma (PMID: 29684080), or childhood-onset leukemia (PMID: 26580448). This variant has been identified in 20/279280 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.
Mendelics	RCV000708856	SCV000837869	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212632	SCV001134454	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28944238 (2017)), ovarian cancer (PMID: 23047549 (2012)), leukemia (PMID: 26580448 (2015)), melanoma (29684080 (2018)), and in several breast cancer cases and control individuals in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00032 (8/24824 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on MSH6 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193124	SCV001361760	likely benign	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.650A>G (p.Asp217Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 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. c.650A>G has been reported in the literature as a VUS/Benign variant in individuals affected with ovarian cancer, pediatric cancer, colorectal cancer, breast cancer (e.g., Pal_2012, Zhang_2015, DeRycke_2017, Guindalini_2022) or in non-cancer controls (e.g. Okawa_2023). These report(s) 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: 28944238, 35264596, 36243179, 23047549, 26580448). ClinVar contains an entry for this variant (Variation ID: 142305). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001193124	SCV002069365	uncertain significance	not specified	2018-07-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131354	SCV002536340	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411184	SCV004018964	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. 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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193124	SCV004243580	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708856	SCV004836752	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 217 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 observed in individuals affected with ovarian cancer (PMID: 23047549), colorectal cancer (PMID: 28944238), melanoma (PMID: 29684080), or childhood-onset leukemia (PMID: 26580448). This variant has been identified in 20/279280 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	RCV001355774	SCV001550749	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Asp217Gly variant was identified in 1 of 3786 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs554012110) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl), databases. The variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 20 of 273722 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 8 of 23898 chromosomes (freq: 0.0003), European Non-Finnish in 3 of 125846 chromosomes (freq: 0.00002), and South Asian in 9 of 30740 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Asp217 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535792	SCV001749951	not provided	Hereditary nonpolyposis colon cancer		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-10-2020 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.