Submissions for variant NM_000179.3(MSH6):c.2667G>T (p.Gln889His)

gnomAD frequency: 0.00048  dbSNP: rs149945495

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034496	SCV000149302	likely benign	not provided	2021-01-22	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: 26689913, 27060149, 22703879, 23621914, 28503720, 28767289, 32659497)
Ambry Genetics	RCV000115393	SCV000185458	likely benign	Hereditary cancer-predisposing syndrome	2021-10-26	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080247	SCV000254299	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000410628	SCV000488488	uncertain significance	Lynch syndrome 5	2016-04-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000235185	SCV000595854	uncertain significance	not specified	2017-01-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034496	SCV000601536	likely benign	not provided	2023-05-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115393	SCV000685307	likely benign	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	clinical testing
Mendelics	RCV003492327	SCV000837901	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410628	SCV001761617	uncertain significance	Lynch syndrome 5	2021-07-22	criteria provided, single submitter	clinical testing	The MSH6 c.2667G>T (p.Gln889His) missense change has a maximum subpopulation frequency of 0.15% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48027789-G-T). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an African American woman diagnosed with breast cancer before 40 years whose family history includes a paternal grandfather with pancreatic cancer (PMID: 28503720) and at least one individual with pancreatic ductal adenocarcinoma (PMID: 28767289, 32659497). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met.
Sema4, Sema4	RCV000115393	SCV002535759	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235185	SCV002765950	likely benign	not specified	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2667G>T (p.Gln889His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 0.0001 in 251964 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11.26 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 African or African-American origin. c.2667G>T has been reported in the literature in two African-American individuals, one affected with breast cancer (Rummel_2017) and one with pancreatic cancer (Shindo_2017). The variant has also been reported in other individuals with breast cancer, without strong evidence of causality (Guindalini_2022). 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: 22703879, 23621914, 28503720, 28767289, 33471991, 35264596). ClinVar contains an entry for this variant (Variation ID: 41591). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV000410628	SCV004019083	benign	Lynch syndrome 5	2023-03-30	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: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115393	SCV004228146	benign	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034496	SCV000043359	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034496	SCV001549812	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Gln889His variant was identified in 3 of 12170 proband chromosomes (frequency: 0.0003) from individuals or families with atherosclerosis or breast cancer (Johnston 2012, Lu 2015, Rummel 2017). The variant was also identified in dbSNP (ID: rs149945495) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters), and in MutDB, databases. The variant was not identified in COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors, databases. The variant was identified in control databases in 36 of 276358 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 35 of 23982 chromosomes (freq: 0.002), Other in 1 of 6448 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln889 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
PreventionGenetics, part of Exact Sciences	RCV004739319	SCV005359257	likely benign	MSH6-related disorder	2024-09-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).