Submissions for variant NM_000179.3(MSH6):c.2962C>T (p.Arg988Cys)

gnomAD frequency: 0.00001  dbSNP: rs61753795

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000232002	SCV000283775	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 988 of the MSH6 protein (p.Arg988Cys). This variant is present in population databases (rs61753795, gnomAD 0.004%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 237172). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000483401	SCV000567197	uncertain significance	not provided	2022-09-30	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 one family suspected of having Lynch syndrome, as well as an individual with breast cancer (Lagerstedt-Robinson et al., 2016; Eygelaar et al., 2022); This variant is associated with the following publications: (PMID: 23621914, 28494185, 17531815, 21120944, 35039564, 27601186)
Ambry Genetics	RCV000571603	SCV000662395	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.R988C variant (also known as c.2962C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2962. The arginine at codon 988 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was previously identified in a Swedish family with Lynch syndrome, but clinical details were not provided (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). In another study, this variant was detected in 1/165 colorectal cancer and/or polyposis patients and was not identified in 2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant has also been reported in a South African patient with early onset infiltrating ductal carcinoma, but no family history information was provided (Eygelaar D et al. Sci Rep, 2022 Jan;12:802). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571603	SCV000690305	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 988 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 breast cancer (PMID: 35039564), and in individuals affected with Lynch syndrome and colorectal cancer (PMID: 27601186, 30267214). This variant has been identified in 5/248524 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483401	SCV001134418	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000571603	SCV002535782	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-26	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265702	SCV002547889	uncertain significance	not specified	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2962C>T (p.Arg988Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A computer modelling approach for predicting the impact of MSH6 variants on protein function scored the variant as likely to impair function (Terui_2013) however, to our knowledge this has not yet been tested by a functional assay. The variant allele was found at a frequency of 1.8e-05 in 217122 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2962C>T has been reported in the literature in an individual with breast cancer (Eygelaar_2022) and an individual with suspected Lynch Syndrome (Lagerstedt-Robinson_2016). However, these report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003463641	SCV004197657	uncertain significance	Endometrial carcinoma	2023-10-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998724	SCV004839100	uncertain significance	Lynch syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 988 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 breast cancer (PMID: 35039564), and in individuals affected with Lynch syndrome and colorectal cancer (PMID: 27601186, 30267214). This variant has been identified in 5/248524 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.