Submissions for variant NM_000179.3(MSH6):c.3724C>T (p.Arg1242Cys)

dbSNP: rs587779285

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218524	SCV000276502	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-02	criteria provided, single submitter	clinical testing	The p.R1242C variant (also known as c.3724C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3724. The arginine at codon 1242 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in an individual diagnosed with diffuse gastric cancer (Henn J et al. Hered Cancer Clin Pract. 2019 Jan;17:5). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer after age 50 (Tung N et al. Cancer. 2015 Jan;121:25-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001243869	SCV001417055	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-18	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 1242 of the MSH6 protein (p.Arg1242Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 232375). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. This variant disrupts the p.Arg1242 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24763289, 28514183, 31204389). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV003322762	SCV004028079	uncertain significance	not provided	2023-08-17	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; This variant is associated with the following publications: (PMID: 25111426, 17531815, 21120944, 25186627, 30680046, 30982232, 31204389, 28514183, 24763289)
Baylor Genetics	RCV003462494	SCV004195768	uncertain significance	Endometrial carcinoma	2023-05-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997965	SCV004835120	uncertain significance	Lynch syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1242 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 gastric cancer (PMID: 30680046), and in individuals affected with breast and/or ovarian cancer (PMID: 25186627, 30982232). This variant has been identified in 1/251188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.3725G>A (p.Arg1242His), c.3724C>A (p.Arg1242Ser), and c.3724C>G (p.Arg1242Gly), are considered to be disease-causing (ClinVar variation ID: 140866, 89449, 455280), suggesting that arginine at this position is important for the protein function. 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.