Submissions for variant NM_000179.3(MSH6):c.148T>C (p.Trp50Arg)

gnomAD frequency: 0.00001  dbSNP: rs374597395

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166759	SCV000217572	likely benign	Hereditary cancer-predisposing syndrome	2019-03-29	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.
Invitae	RCV000203855	SCV000261867	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166759	SCV000904012	likely benign	Hereditary cancer-predisposing syndrome	2018-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001548024	SCV001767869	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23621914)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281987	SCV002570526	uncertain significance	not specified	2022-07-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.148T>C (p.Trp50Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A bioinformatics analysis supports that this missense variant does not alter protein structure (example: Terui_2013). The variant allele was found at a frequency of 9.9e-06 in 201732 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.148T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001358151	SCV004828064	likely benign	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358151	SCV001553814	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Trp50Arg variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs374597395) as "With Likely benign allele", ClinVar (classified as likely benign by Ambry Genetics and Invitae), and in UMD-LSDB (1x) databases. The variant was identified in control databases in 2 of 199148 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant identified in European population in 2 of 84074 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Trp50 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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. 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.