Submissions for variant NM_000179.3(MSH6):c.1082G>A (p.Arg361His)

gnomAD frequency: 0.00002  dbSNP: rs63750440

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409637	SCV000489034	uncertain significance	Lynch syndrome 5	2016-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000487116	SCV000571658	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1082G>A at the cDNA level, p.Arg361His (R361H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant was observed in an individual with a personal history of hepatic and gastric cancer (Koehler 2007). MSH6 Arg361His was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Arg361His is located in the nuclear localization signals region (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Arg361His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000567227	SCV000670019	likely benign	Hereditary cancer-predisposing syndrome	2024-02-01	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.
Color Diagnostics, LLC DBA Color Health	RCV000567227	SCV000690172	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV000701439	SCV000830240	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074629	SCV000887361	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.1082G>A has a 48.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, and 0.16 to 1, generated from evidence of seeing this as a somatic mutation in three independent tumors two without loss of heterozygosity and one with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
CeGaT Center for Human Genetics Tuebingen	RCV000487116	SCV002585789	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	MSH6: PM2, BP4
Myriad Genetics, Inc.	RCV000409637	SCV004019092	uncertain significance	Lynch syndrome 5	2023-03-30	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003466931	SCV004195529	uncertain significance	Endometrial carcinoma	2023-09-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074629	SCV004842902	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hepatic carcinoma and gastric cancer (PMID: 17498565). This variant has also been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.