Submissions for variant NM_000179.3(MSH6):c.3788G>A (p.Arg1263His)

gnomAD frequency: 0.00010  dbSNP: rs147852216

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656903	SCV000149332	likely benign	not provided	2021-03-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23621914, 27498913, 24728327, 25186627)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079217	SCV000254321	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115423	SCV000292204	uncertain significance	Hereditary cancer-predisposing syndrome	2025-03-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1263 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with breast cancer (PMID: 25186627, 33471991), but has also been observed in unaffected individuals (PMID: 4728327, 32885271, 32980694, 33471991). This variant has been identified in 47/282612 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.
Ambry Genetics	RCV000115423	SCV000580213	likely benign	Hereditary cancer-predisposing syndrome	2021-04-06	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.
Counsyl	RCV000662548	SCV000785130	uncertain significance	Lynch syndrome 5	2017-05-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656903	SCV000889494	uncertain significance	not provided	2023-12-05	criteria provided, single submitter	clinical testing	The MSH6 c.3788G>A (p.Arg1263His) variant has been reported in individuals with breast cancer (PMIDs: 25186627 (2015) and 33471991 (2021), see also http://databases.lovd.nl/shared/genes/MSH6)), and a Lynch syndrome-associated cancer (PMID: 31391288 (2020)). This variant has also been identified in unaffected individuals (PMIDs: 24728327 (2014), 32980694 (2020), 32885271 (2021), 33471991 (2021), http://databases.lovd.nl/shared/genes/MSH6). The frequency of this variant in the general population, 0.00085 (26/30612 chromosomes in South Asian 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764435	SCV000895492	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115423	SCV002528064	likely benign	Hereditary cancer-predisposing syndrome	2020-12-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121588	SCV002552365	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000662548	SCV003915720	uncertain significance	Lynch syndrome 5	2023-04-07	criteria provided, single submitter	clinical testing	A heterozygous missense substitution (p.Arg1263His) lies in exon 8 of the MSH6 gene and alters a conserved residue in the protein. . The in silico prediction of the variant are possibly damaging by LRT, Mutation Taster and SIFT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as variant of uncertain significance.
Myriad Genetics, Inc.	RCV000662548	SCV004019037	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is 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].
Neuberg Centre For Genomic Medicine, NCGM	RCV000662548	SCV005382494	uncertain significance	Lynch syndrome 5	2023-05-20	criteria provided, single submitter	clinical testing	The missense variant c.3788G>A (p.Arg1263His) in the MSH6 gene has been reported previously in individuals affected with Lynch syndrome (Bodian et al., 2014; Terui et al., 2013). This variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and absent in 1000 Genomes. The amino acid Arginine at position 1263 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg1263His in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. The recent data however suggests that this could be a Likely benign variant with limited evidence.
Mendelics	RCV005229905	SCV005880327	likely benign	Hereditary cancer	2025-02-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
ITMI	RCV000121588	SCV000085784	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656903	SCV001552473	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Arg1263His variant was identified in 10 of 1362 chromosomes (frequency: 0.007) from an ancestrally diverse cohort of healthy individuals the literature (Bodian_2014_24728327). The variant was identified in dbSNP (ID: rs147852216) “With Uncertain significance allele”, ClinVar (5x as uncertain significance by GeneDx, Invitae, Color Genomics, Ambry Genetics, ITMI), Clinvitae (3x), and in control databases in 46 of 276952 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24026 chromosomes (freq: 0.00004), Other in 3 of 6460 chromosomes (freq: 0.0005), Latino in 10 of 34386 chromosomes (freq: 0.0003), European Non-Finnish in 7 of 126488 chromosomes (freq: 0.00006), and South Asian in 25 of 30782 chromosomes (freq: 0.0008) while not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations. The variant was not identified in the Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The p.Arg1263 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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.