Submissions for variant NM_000179.3(MSH6):c.1730G>A (p.Arg577His)

gnomAD frequency: 0.00009  dbSNP: rs376220212

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131162	SCV000186106	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The p.R577H variant (also known as c.1730G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1730. The arginine at codon 577 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in cohorts of breast and endometrial cancer patients (Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Ring KL et al. Mod Pathol. 2016 Nov;29(11):1381-1389; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; erner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). However, this variant was also identified in a cohort of 681 ancestrally diverse, healthy subjects under the age of 50 (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). This alteration (designated as rs376220212) also co-occurred with an MSH2 missense alteration in one of 25 asymptomatic adults undergoing whole exome sequencing; this individual was found to have two tubulovillous adenomas at age 50 (Pillar N et al. Mol. Genet. Genomic Med. 2015 Sep;3:433-9). The p.R577H variant was classified as deleterious by authors who identified it in a CDKN2A mutation positive patient with pancreatic cancer and in 0 of 1001 controls. This determination, however, was made based on the meta likelihood ratio prediction tool incorporating in silico algorithms and allele frequency only (Yang XR et al. Hum. Genet. 2016 Nov;135:1241-1249). 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.
GeneDx	RCV000587914	SCV000211347	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with pancreatic, endometrial, breast, and other cancers (Lu et al., 2015; Ring et al., 2016; Yang et al., 2016; Lerner-Ellis et al., 2021; Sandoval et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 26510091, 34011629, 31253177, 24728327, 23621914, 26546047, 27449771, 27443514, 26689913, 25363768, 31104363, 26436109, 31785789, 21120944, 17531815, Giacomazzi2022[preprint], 35264596, 35982160, 35982159, 32885271, 33606809, 25085752, 23729658)
Invitae	RCV000204422	SCV000260364	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000410866	SCV000488474	uncertain significance	Lynch syndrome 5	2016-04-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131162	SCV000685223	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 577 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 performed for this variant. This variant has been reported in individuals affected with endometrial, pancreatic and breast cancer (PMID: 26689913, 27443514, 27449771, 32885271, 33606809) and an unaffected individual (PMID: 24728327). This variant has been identified in 10/250236 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	RCV000121579	SCV000695793	uncertain significance	not specified	2019-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1730G>A (p.Arg577His) results in a non-conservative amino acid change in 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 4e-05 in 250236 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4e-05 vs 0.00014), allowing no conclusion about variant significance. c.1730G>A has been reported in the literature in individuals affected with tubulovillous adenomas, endometrial carcinoma or pancreatic cancer (Pillar_2015, Ring_2016, Yang_2016). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.2677_2678delCT, p.Leu893AlafsX6), providing supporting evidence for a benign role. Six 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.
Mendelics	RCV000708870	SCV000837886	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587914	SCV002010114	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587914	SCV002047260	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 32885271 (2021), 33471991 (2021), 33606809 (2021), and 35264596 (2022)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 27449771 (2016)), tubulovillous adenomas (PMID: 26436109 (2015)), and autism (PMIDs: 34011629 (2021), 31785789 (2019), and 25363768 (2014)). In addition, this variant has been reported in control individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000087 (3/34586 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001762265	SCV003807888	uncertain significance	Endometrial carcinoma	2022-11-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting
Myriad Genetics, Inc.	RCV000410866	SCV004019011	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410866	SCV004171399	uncertain significance	Lynch syndrome 5	2023-11-13	criteria provided, single submitter	clinical testing	The MSH6 c.1730G>A (p.Arg577His) missense change has a maximum subpopulation frequency of 0.0087% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported in individuals affected with endometrial, pancreatic, ovarian, and breast cancer (PMID: 26689913, 27443514, 27449771, 32885271, 33606809), and it has also been observed in an unaffected individual (PMID: 24728327). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV001762265	SCV004197703	uncertain significance	Endometrial carcinoma	2023-09-25	criteria provided, single submitter	clinical testing
ITMI	RCV000121579	SCV000085775	not provided	not specified	2013-09-19	no assertion provided	reference population
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249972	SCV001423986	likely pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355523	SCV001550435	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg577His variant was identified in a study of 114 cancer susceptibility genes, in individuals with 12 different cancer types, in 1 of 8068 proband chromosomes (frequency: 0.0001) from individuals or families with lung adenocarcinoma (Lu 2015) and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014). The variant was also identified in dbSBP (ID: rs376220212) as “With Uncertain significance allele,” ClinVar (as uncertain significance), Clinvitae (as uncertain significance), Cosmic, UMD-LSDB (co-occurring with a pathogenic MSH6 variant p.Leu893AlafsX6), as well as in our laboratory co-occurring with a pathogenic APC variant (p.Tyr1027IlefsX10), increasing the likelihood that the p.Arg577His variant does not have clinical significance. The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 10 of 245960 chromosomes at a frequency of 0.000041 in the following populations: African in 1 of 15286 chromosomes (freq. 0.000065), Latino in 3 of 33578 chromosomes (freq. 0.000089), and European (Non-Finnish) in 6 of 111440 chromosomes (freq. 0.00005) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg577His residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein MutS, connector domain DNA mismatch repair protein MSH6 functional domain(s) increasing the likelihood that it may have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.