Submissions for variant NM_000179.3(MSH6):c.3162C>T (p.Ile1054=)

dbSNP: rs149605979

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163126	SCV000213638	likely benign	Hereditary cancer-predisposing syndrome	2015-09-23	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	RCV001087949	SCV000260097	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000423495	SCV000513696	benign	not specified	2015-04-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000163126	SCV000690318	likely benign	Hereditary cancer-predisposing syndrome	2017-07-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679232	SCV000805877	likely benign	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000423495	SCV000889485	benign	not specified	2022-06-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423495	SCV001363906	likely benign	not specified	2019-12-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679232	SCV001472289	likely benign	not provided	2019-10-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163126	SCV002535798	likely benign	Hereditary cancer-predisposing syndrome	2021-03-19	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995235	SCV004837213	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357025	SCV001552349	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Ile1054= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs149605979) as “With Likely benign allele” , ClinVar (as benign by Gene Dx and likely benign by Ambry Genetics, Invitae, and Quest Diagnostics), Clinvitae (3x as benign and likely benign), and Cosmic (1x in bile duct carcinoma) databases. The variant was identified in control databases in 26 of 272178 chromosomes at a frequency of 0.000096 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 20 of 23926 chromosomes (freq: 0.000836), Latino in 1 of 34350 chromosomes (freq: 0.000029), European (Non-Finnish) in 1 of 125540 chromosomes (freq: 0.000008), East Asian in 2 of 18794 chromosomes (freq: 0.000106), European (Finnish) in 2 of 22290 chromosomes (freq: 0.00009), while the variant was not observed in the Other, Ashkenaz iJewish, and South Asian populations. The p.Ile1054= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.