ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1730G>A (p.Arg577His) (rs376220212)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131162 SCV000186106 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-01 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 a breast cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas and in a cohort of 381 unselected 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). However, this variant was 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 2021-10-25 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, and other cancers (Lu 2015, Ring 2016, Yang 2016); This variant is associated with the following publications: (PMID: 26510091, 34011629, 31253177, 24728327, 23621914, 26546047, 27449771, 27443514, 26689913, 25363768, 31104363, 21120944, 17531815, 26436109)
Invitae RCV000204422 SCV000260364 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 577 of the MSH6 protein (p.Arg577His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs376220212, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 26689913) and pancreatic cancer (PMID: 27449771). This variant has been reported to co-occur with a pathogenic variant in MSH6 in one individual in the Universal Mutation Database (PMID: 23729658). While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that the c.1730G>A variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 134852). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. Neither of these predictions has been confirmed by published functional studies. 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.
Counsyl RCV000410866 SCV000488474 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-04-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131162 SCV000685223 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-23 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) 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
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.

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