Submissions for variant NM_000179.3(MSH6):c.1054G>A (p.Val352Ile)

gnomAD frequency: 0.00007  dbSNP: rs730881787

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656893	SCV000211271	likely benign	not provided	2021-01-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25111426, 28135145)
Ambry Genetics	RCV000160662	SCV000212768	likely benign	Hereditary cancer-predisposing syndrome	2019-05-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga)	RCV000656893	SCV000230040	uncertain significance	not provided	2014-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV001082336	SCV000283697	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003323296	SCV000837876	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160662	SCV000902890	likely benign	Hereditary cancer-predisposing syndrome	2016-06-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780471	SCV000917744	likely benign	not specified	2022-07-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1054G>A (p.Val352Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251198 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1054G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or breast cancer. However, a recent case-control study indicates that this variant is not associated with breast cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=5, VUS n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000986713	SCV001297401	uncertain significance	Lynch syndrome 5	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656893	SCV001469561	likely benign	not provided	2022-08-15	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656893	SCV002010121	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000160662	SCV004014883	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing