Submissions for variant NM_000179.3(MSH6):c.596C>T (p.Pro199Leu)

dbSNP: rs587782315

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131212	SCV000186162	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-01	criteria provided, single submitter	clinical testing	The p.P199L variant (also known as c.596C>T), located in coding exon 3 of the MSH6 gene, results from a C to T substitution at nucleotide position 596. The proline at codon 199 is replaced by leucine, an amino acid with similar properties. This variant was detected in a patient with uterine cancer diagnosed at age 75 that demonstrated loss of MSH6 on immunohistochemistry (IHC) and was classified as a variant of unknown significance by the authors. This patient was also found to have a germline MLH1 p.N570S alteration also classified as a variant of unknown significance (Frolova AI et al. Gynecol Oncol, 2015 Apr;137:7-13). 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.
Invitae	RCV000477097	SCV000551093	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131212	SCV000685504	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 199 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 uterine papillary serous carcinoma that displayed loss of MSH6 protein via immunohistochemistry and who had a family history of Lynch syndrome-associated cancer (PMID: 25617771), as well as in an individual affected with an unspecified cancer having clinical features of Lynch syndrome (PMID: 31391288). This variant has been identified in 1/251398 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.
GeneDx	RCV002510790	SCV002820554	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with uterine cancer, which showed loss of MSH6 protein on immunohistochemistry analysis (Frolova et al., 2015); This variant is associated with the following publications: (PMID: 30246500, 25617771)
All of Us Research Program, National Institutes of Health	RCV003998091	SCV004841093	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 199 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 uterine papillary serous carcinoma that displayed loss of MSH6 protein via immunohistochemistry and who had a family history of Lynch syndrome-associated cancer (PMID: 25617771), as well as in an individual affected with an unspecified cancer having clinical features of Lynch syndrome (PMID: 31391288). This variant has been identified in 1/251398 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.