Submissions for variant NM_000179.3(MSH6):c.1857A>C (p.Glu619Asp)

gnomAD frequency: 0.00005  dbSNP: rs63751121

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132230	SCV000187313	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	The p.E619D variant (also known as c.1857A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1857. The glutamic acid at codon 619 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was reported in conjunction with a pathogenic mutation in MSH6 in an individual diagnosed with MSI-H colon cancer demonstrating absent MSH6 on IHC. This alteration was found to be in cis with the pathogenic mutation. The pathogenic mutation was found to be de novo in this individual, while the p.E619D alteration was paternally inherited (Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94). This alteration has also been reported in a Polish individual with metachronous bilateral breast cancer diagnosed at ages 57 and 73 years and endometrial cancer diagnosed at age 75 years. The only reported family history of cancer was a sister diagnosed with liver cancer at age 74 and a sister diagnosed with gallbladder cancer at an unknown age. This proband's tumor was not tested by IHC and no family members were tested for this alteration (Suchy J et al. Clin. Genet. 2006 Jul;70:68-70). This variant was also previously detected in a Spanish patient with a strong family history of pancreatic cancer (Earl J et al. EBioMedicine, 2020 Mar;53:102675). In addition, this alteration has been identified in at least one Swedish family with a history of Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). This amino acid position is highly 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	RCV000221704	SCV000279342	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including colorectal, pancreatic, and unspecified Lynch syndrome-related cancer (Plaschke et al., 2004; Lagerstedt-Robinson et al., 2016; Earl et al., 2020); the variant was also identified in an individual with breast and endometrial cancer in whom tumor studies revealed presence of all mismatch repair proteins and microsatellite stability in the endometrial tumor (Suchy et al., 2006); This variant is associated with the following publications: (PMID: 16813607, 15483016, 23621914, 27601186, 17531815, 21120944, 32113160, 26934580, 27930734, 36897649)
Invitae	RCV000524122	SCV000551282	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132230	SCV000685234	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 619 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 27601186), an individual affected with colorectal cancer who carried a pathogenic mutation in the same gene (PMID: 15483016), an individual affected with breast and endometrial cancer with tumor showing microsatellite stability and normal MSH6 gene expression (PMID: 16813607), and an individual affected with pancreatic cancer (PMID: 32113160) . This variant has been identified in 5/282082 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000221704	SCV002010112	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460665	SCV004197593	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997069	SCV004835445	uncertain significance	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 619 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 27601186), an individual affected with colorectal cancer who carried a pathogenic mutation in the same gene (PMID: 15483016), an individual affected with breast and endometrial cancer with tumor showing microsatellite stability and normal MSH6 gene expression (PMID: 16813607), and an individual affected with pancreatic cancer (PMID: 32113160) . This variant has been identified in 5/282082 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.