Submissions for variant NM_000179.3(MSH6):c.2702G>A (p.Arg901His)

gnomAD frequency: 0.00001  dbSNP: rs63749889

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000559913	SCV000624787	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570122	SCV000662366	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	The p.R901H variant (also known as c.2702G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2702. The arginine at codon 901 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in conjunction with a protein-truncating MLH1 mutation in a proband diagnosed with both endometrial and colon cancer whose mother had early-onset colon cancer (Charames GS et al. Hum Genet. 2000 Dec;107(6):623-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001561918	SCV001784607	uncertain significance	not provided	2019-09-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a personal history of colon and endometrial cancer who was also found to harbor a MLH1 pathogenic variant (Charames 2000).; This variant is associated with the following publications: (PMID: 23621914, 26333163, 11153917)
Baylor Genetics	RCV003460671	SCV004195647	uncertain significance	Endometrial carcinoma	2023-07-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570122	SCV004357669	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 901 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 pancreatic cancer (PMID: 32980694). This variant was also reported in an individual affected with colorectal and endometrial cancer, however, they also carried a pathogenic MLH1 variant (reported as 397delT, fs400stop; PMID: 11153917) that could explain the observed phenotype. This variant has been identified in 7/282034 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in the 4/13855 Chinese population samples (PMID: 34172528). 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.
All of Us Research Program, National Institutes of Health	RCV003997081	SCV004840728	uncertain significance	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 901 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 pancreatic cancer (PMID: 32980694). This variant was also reported in an individual affected with colorectal and endometrial cancer, however, they also carried a pathogenic MLH1 variant (reported as 397delT, fs400stop; PMID: 11153917) that could explain the observed phenotype. This variant has been identified in 7/282034 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in the 4/13855 Chinese population samples (PMID: 34172528). 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.