Submissions for variant NM_000179.3(MSH6):c.2027A>G (p.Lys676Arg)

gnomAD frequency: 0.00001  dbSNP: rs143643688

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131641	SCV000186666	likely benign	Hereditary cancer-predisposing syndrome	2019-04-09	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.
GeneDx	RCV000212656	SCV000211287	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast and/or pancreatic cancer (PMID: 25479140, 25186627, 33471991, 34326862); This variant is associated with the following publications: (PMID: 23621914, 25186627, 25479140, 33471991, 34326862, 17531815, 21120944)
Invitae	RCV000204601	SCV000261183	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000410949	SCV000489141	uncertain significance	Lynch syndrome 5	2016-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131641	SCV000902971	likely benign	Hereditary cancer-predisposing syndrome	2015-11-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131641	SCV002535693	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410949	SCV004019038	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].
Baylor Genetics	RCV003462017	SCV004197582	uncertain significance	Endometrial carcinoma	2023-10-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354229	SCV001548791	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Lys676Arg variant was identified in 1 of 580 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic cancer (Grant_2015_25479140). A bioinformatics tool, CoDP (Combination of the Different Properties) integrating the prediction results of three methods (MAPP, PolyPhen-2 and SIFT) and two structural properties, found the variant did not impact the MSH6 protein (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs143643688) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae and Counsyl), Clinvitae (4x), and in control databases in 15 of 276506 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). Observations by population include Latino in 2 of 34392 chromosomes (freq: 0.00006), European Non-Finnish in 13 of 126094 chromosomes (freq: 0.0001); it was not observed in the African, “Other”, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The p.Lys676 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 the Arg residue has an impact on the protein; however, this information is not predictive enough to rule out 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.