Submissions for variant NM_000179.3(MSH6):c.3104G>T (p.Arg1035Leu)

dbSNP: rs730881801

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160688	SCV000211309	uncertain significance	not provided	2023-05-08	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28002797, 17531815, 21120944)
Invitae	RCV000198759	SCV000254304	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1035 of the MSH6 protein (p.Arg1035Leu). This variant is present in population databases (rs730881801, gnomAD 0.002%). 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: 182641). 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. 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.
Ambry Genetics	RCV000223597	SCV000276589	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The p.R1035L variant (also known as c.3104G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 3104. The arginine at codon 1035 is replaced by leucine, an amino acid with dissimilar properties. In one study, this variant was reported in 6/60,466 breast cancer cases as well as 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Color Diagnostics, LLC DBA Color Health	RCV000223597	SCV000685352	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1035 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with prostate cancer (Duarte 2019 dissertation, University of Sao Paulo). In a large breast cancer case-control study, this variant has been reported in 6/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/248120 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175452	SCV001339018	uncertain significance	not specified	2020-03-20	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3104G>T (p.Arg1035Leu) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248120 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3104G>T in the germline state was reported in individuals affected with Lynch Syndrome, and no experimental evidence demonstrating its impact on protein function have been published. Four 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	RCV003462096	SCV004197681	uncertain significance	Endometrial carcinoma	2023-09-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998500	SCV004837157	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1035 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with prostate cancer (Duarte 2019 dissertation, University of Sao Paulo). In a large breast cancer case-control study, this variant has been reported in 6/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/248120 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.