Submissions for variant NM_000179.3(MSH6):c.364G>A (p.Glu122Lys)

gnomAD frequency: 0.00004  dbSNP: rs143036974

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212630	SCV000211353	likely benign	not provided	2019-01-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23621914)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197561	SCV000254318	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776349	SCV000911715	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780470	SCV000917743	likely benign	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.364G>A (p.Glu122Lys) results in a conservative amino acid change located in the PWWP domain 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 9.5e-05 in 251490 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 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 Latino origin. c.364G>A has been reported in the literature. 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: 23621914, 25419514). ClinVar contains an entry for this variant (Variation ID: 182662). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000776349	SCV001182330	likely benign	Hereditary cancer-predisposing syndrome	2021-06-11	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.
Sema4, Sema4	RCV000776349	SCV002528055	likely benign	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411966	SCV004018882	benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. 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].
Counsyl	RCV000411966	SCV000487888	uncertain significance	Lynch syndrome 5	2015-11-25	flagged submission	clinical testing