Submissions for variant NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp)

gnomAD frequency: 0.00002  dbSNP: rs587781690

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129855	SCV000184672	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.G1186D variant (also known as c.3557G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3557. The glycine at codon 1186 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 7. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was identified in a male proband with Barrett’s esophagus who had a family history of esophageal cancer in a first-degree relative (Rubenstein JH et al. Clin Transl Gastroenterol, 2020 Apr;11:e00151). 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	RCV000206364	SCV000260543	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1186 of the MSH6 protein (p.Gly1186Asp). This variant is present in population databases (rs587781690, gnomAD 0.004%). 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: 141364). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000657043	SCV000567381	uncertain significance	not provided	2018-03-01	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3557G>A at the cDNA level, p.Gly1186Asp (G1186D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly1186Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may destroy the nearby natural splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH6 Gly1186Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000485699	SCV000712797	uncertain significance	not specified	2017-01-25	criteria provided, single submitter	clinical testing	The p.Gly1186Asp variant in MSH6 has not been previously reported in individuals with Lynch syndrome but has been identified in 3/66564 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587781690). This variant is located in the first base of the exon, which is part of the 3? splice region. Splicing prediction tools do not suggest altered s plicing and computational prediction tools and conservation analysis suggest tha t the p.Gly1186Asp variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Gly1186Asp variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657043	SCV000889489	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with Barrett’s esophagus and a family history of esophageal cancer in a first degree relative (PMID: 32251017 (2020)) and in an individual with colon polyps or colorectal cancer (PMID: 31422818 (2019)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases and not among unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000044 (5/112648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764433	SCV000895490	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129855	SCV001354496	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1186 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 performed for this variant. This variant has not been reported in individuals affected with Lynch syndrome or colorectal cancer cancer in the literature. In a large breast cancer case-control study, This variant has been observed in 2/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 5/249444 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.
Sema4, Sema4	RCV000129855	SCV002528047	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485699	SCV004037859	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3557G>A (p.Gly1186Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Two computational tools predict no significant impact on normal splicing and 2 predict the variant weakens the canonical 3' acceptor splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 249444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3557G>A has been reported in the literature in individuals affected with Colorectal Cancer (Gordon_2019), Esophageal Cancer (Rubenstein_2020) and Breast Cancer (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31422818, 32251017, 33471991). Eight ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003460903	SCV004197562	uncertain significance	Endometrial carcinoma	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997530	SCV004835091	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1186 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 performed for this variant. This variant has not been reported in individuals affected with Lynch syndrome or colorectal cancer cancer in the literature. In a large breast cancer case-control study, This variant has been observed in 2/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 5/249444 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.