Submissions for variant NM_000179.3(MSH6):c.3762A>T (p.Glu1254Asp)

gnomAD frequency: 0.00005  dbSNP: rs375459388

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524187	SCV000166234	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000587284	SCV000211327	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26333163, 22290698, 30521064, 30093976)
Ambry Genetics	RCV000160699	SCV000215311	likely benign	Hereditary cancer-predisposing syndrome	2018-09-12	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	RCV000408995	SCV000487880	uncertain significance	Lynch syndrome 5	2015-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160699	SCV000685443	likely benign	Hereditary cancer-predisposing syndrome	2020-02-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212689	SCV000695887	likely benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3762A>T (p.Glu1254Asp) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251194 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 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 East Asian origin. The variant, c.3762A>T, has been reported in the literature in individuals affected with various tumor phenotypes, including colorectal cancer (Lin_2017, Young_2018, Chan_2018, Gong_2019, Dorling_2021), but was also found in several controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.2818C>T (p.Gln940X), in an internal LCA sample), providing supporting evidence for a benign role. 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: 22290698, 30093976, 29945567, 31118792, 32068069, 33471991, 31308508, 31966835). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587284	SCV001134441	likely benign	not provided	2023-05-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160699	SCV002528062	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-21	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000408995	SCV004018969	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
PreventionGenetics, part of Exact Sciences	RCV004537280	SCV004121040	uncertain significance	MSH6-related disorder	2023-08-08	criteria provided, single submitter	clinical testing	The MSH6 c.3762A>T variant is predicted to result in the amino acid substitution p.Glu1254Asp. This variant was reported in an individual with Colorectal cancer, non-polyposis (Jiang et al 2019. PubMed ID: 30521064; Chan GHJ et al 2018. PubMed ID: 30093976). This variant is reported in 0.075% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48033458-A-T), which is more common than expected for a primary cause of disease. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/89457/). Although we suspect this variant may be benign, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997096	SCV004835132	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587284	SCV001549237	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Glu1254Asp variant was identified as a somatic variant in a lung enteric adenocarcinoma sample (Lin 2017) and in a patient affected with Lynch syndrome, classified as a neutral variant by in silico models (Ali 2012). The variant was also identified in dbSNP (ID: rs375459388) as “With other allele”, ClinVar (as uncertain significance by InSiGHT, Invitae, GeneDx, Counsyl, Color Genomics, and Integrated Genetics, and as likely benign by Ambry Genetics), and Insight Colon Cancer Gene Variant Database (as uncertain significance). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 15 of 276930 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6460 chromosomes (freq: 0.0002), European (Non-Finnish) in 1 of 126480 chromosomes (freq: 0.000008), and East Asian in 13 of 18866 chromosomes (freq: 0.0007). The East Asian allele frequency is 3 times greater than the maximal expected frequency of a pathogenic MSH6 allele (0.0002), increasing the likelihood that this may be a low frequency benign variant in the East Asian population. The variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish, o South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Glu1254 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. 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.