ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3961A>G (p.Arg1321Gly) (rs41295278)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590664 SCV000149334 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3961A>G at the cDNA level, p.Arg1321Gly (R1321G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has been reported in individuals with early-onset colorectal cancer (CRC), pancreatic cancer, and in one individual with a personal history of Lynch syndrome-associated cancer and/or polyps (Pinto 2006, Barneston 2008, Yurgelun 2015, Jansen 2016, Shindo 2017). This variant was also reported to co-occur with an MSH2 pathogenic deletion in a patient with mismatch repair-deficient CRC (Le 2017). MSH6 Arg1321Gly was observed at an allele frequency of 0.03% (35/124,972) in individuals of European ancestry in large population cohorts (Lek 2016). MSH6 Arg1321Gly is located within an MSH2 binding site and the ATPase domain (Kariola 2002, Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg1321Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115425 SCV000186831 likely benign Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV001082577 SCV000283832 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000410058 SCV000487938 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115425 SCV000685469 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 1321 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 Lynch syndrome–associated cancer and/or polyps, pancreatic, kidney, uterine, omentum cancer, and glioblastoma (PMID: 16940983, 18033691, 25980754, 26648449, 26689913, 28767289, 29596542, 29684080, 31422818, 31391288), including one case with a pathogenic MSH2 covariant (PMID: 25980754). This variant has also been identified in 39/279718 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 RCV000202255 SCV000695903 likely benign not specified 2020-07-22 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3961A>G (p.Arg1321Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal (IPR000432) domain, comprised of the ATPase domain and the HTH (helix-turn-helix) domain, the latter being involved in dimer contacts (InterPro) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 283676 control chromosomes (gnomAD and publication data). The variant was predominantly at a frequency of 0.00027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3961A>G has been reported in the literature in individuals affected with Lynch Syndrome, colorectal cancer (Pinto 2006, Barneston 2008, Yurgelun 2015, Jansen 2016, Gordon_2019), Cowden/Cowden-like (CS/CS-like) or Bannayan-Riley-Ruvalcaba syndromes (Yehia 2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer (i.e. lack of co-segregation data). UMD database reported the variant in 3 patients and one patient was indicated to carry another pathogenic MSH6 variant (c.3514dup, p.Arg1172LysfsX5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (8x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000202255 SCV000712603 uncertain significance not specified 2019-05-08 criteria provided, single submitter clinical testing The p.Arg1321Gly variant in MSH6 has been reported in at least 2 individuals with colorectal cancer (Pinto 2006, Barnetson 2008), in 1 individual with suspected Lynch syndrome (Yurgelun 2015) and in an individual with pancreatic cancer and a family history of various cancers (Shindo 2017). It has also been found in one individual who had a second pathogenic variant in MSH6 (p.Arg1172fs, Universal Mutation Database http://139.124.156.133/4D_molecules/UMD224708.html) and one individual who carried two additional variants in MSH2 (p.Tyr165Asp and p.Asn596del, InSiGHT database http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php), although no clinical information is available for these individuals. It has also been identified in 34/127446 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Uncertain significance on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89490). Computational prediction tools (Terui 2013) and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain.
PreventionGenetics,PreventionGenetics RCV000590664 SCV000805900 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing
Mendelics RCV000074958 SCV000837926 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000074958 SCV000891047 uncertain significance Lynch syndrome 2020-10-19 criteria provided, single submitter clinical testing The MSH6 c.3961A>G (p.Arg1321Gly) missense change has a maximum subpopulation frequency of 0.027% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48033750-A-G). Five of seven in silico tools predict a damaging effect of this variant on protein function (PP3), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 16940983, 18033691) and an individual with suspected Lynch syndrome (PMID: 25980754). It has also been reported in an individual with pancreatic ductal adenocarcinoma and family history of miscellaneous cancer types (PMID: 28767289). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590664 SCV001134448 likely benign not provided 2019-03-07 criteria provided, single submitter clinical testing
Mendelics RCV000410058 SCV001135853 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148646 SCV000190361 uncertain significance Colorectal cancer, early onset 2014-06-01 no assertion criteria provided research
Mayo Clinic Laboratories, Mayo Clinic RCV000202255 SCV000257289 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355442 SCV001550328 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Arg1321Gly variant was identified in 3 of 2112 proband chromosomes (frequency: 0.0014) from individuals or families with colorectal cancer and was not identified in 2676 control chromosomes from healthy individuals (Bameston 2008, Le 2017, Pinto 2006). The variant was also identified in the following databases: dbSNP (ID: rs41295278) as With Uncertain significance allele, ClinVar (classified as uncertain significance by InSight, Genedx, Ambry Genetics, Counsyl, Mayo Clinic; as likely benign by Invitae), Clinvitae (classified as uncertain significance by ClinVar), MutDB (classified as polymorphism), UMD-LSDB (3X neutral), Insight Colon Cancer Gene Variant Database (8X class3), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (9X). In UMD the variant was identified with a co-occurring pathogenic MSH6 variant (c.3514dup (p.Arg1172LysfsX5)), increasing the likelihood that the p.Arg1321Gly variant does not have clinical significance. The variant was not identified in the COGR, Cosmic, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 40 of 274126 chromosomes at a frequency of 0.0002 in the following populations: African in 1 of 23864 chromosomes (freq. 0.00004), other in 2 of 6418 chromosomes (freq. 0.0003), European in 35 of 124972 chromosomes (freq. 0.0003), increasing the likelihood that this may be a low frequency increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg1321 residue is conserved in mammals but not in more distantly related 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the DNA mismatch repair protein MutS, C-terminal P-loop containing nucleoside triphosphate hydrolase and DNA mismatch repair Msh6 functional domains. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000590664 SCV001740992 uncertain significance not provided no assertion criteria provided clinical testing

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