ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1A>C (p.Met1Leu) (rs267607911)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076334 SCV000107358 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Insufficient evidence
Invitae RCV000524369 SCV000166271 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-11-01 criteria provided, single submitter clinical testing This variant affects the initiator methionine of the MSH2 mRNA. It has been shown to result in multiple encoded protein products, including the full length protein and a protein lacking the first 25 amino acid residues (PMID: 21837758). This variant is present in population databases (rs267607911, ExAC 0.03%). This variant has been reported in patients with squamous cell carcinoma, ovarian, pancreatic, gastric and colorectal cancers (PMID: 21837758, 23047549, 18033691, 10874307, 25479140, 28944238, 26270727, 29706558). It has also been reported in trans with a pathogenic MSH2 variant in an individual who did not present with constitutional mismatch repair deficiency syndrome, which suggests that this c.1A>C substitution in MSH2 was not the primary cause of disease in that individual (PMID: 25639900). ClinVar contains an entry for this variant (Variation ID: 90832). Functional analyses of a recombinant MSH2 protein lacking the first 25 residues found that the truncated protein was capable of binding to MSH6 but had a slightly reduced activity compared to the wild type complex (PMID: 21837758). The clinical significance of these findings is unknown. 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 RCV000656870 SCV000211183 uncertain significance not provided 2020-09-02 criteria provided, single submitter clinical testing Initiator codon variant shown to produce multiple protein products including a full-length and a truncated transcript missing the first 25 amino acids through use of an in-frame alternate start codon (Cyr 2012); Published functional studies are inconclusive: Demonstrated impaired DNA binding and mismatch repair activity, but had no effect on MSH6 or MSH3 interaction (Cyr 2012); Observed in individuals with MSH2-related cancers; however, tumor studies have shown microsatellite stability (MSS) or low levels of instability (MSI-L), and no loss of MSH2 protein expression (Otway 2000, Parc 2003, Barnetson 2006, Barnetson 2008, Pal 2012, Cyr 2012, Chubb 2015, Grant 2015, Fewings 2018); This variant is associated with the following publications: (PMID: 12624141, 27476653, 21837758, 10874307, 16807412, 18033691, 18781192, 25639900, 23047549, 27064304, 24302565, 27153395, 28779004, 27449771, 28944238, 9718327, 25479140, 25559809, 29706558, 30728895, 26270727, 29625052, 32338768)
Ambry Genetics RCV000160588 SCV000214177 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the MSH2 gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts including ovarian cancer, pancreatic cancer, early-onset colorectal cancer (diagnosed under age 30), and known or suspected Lynch syndrome cases; however, tumors do not consistently demonstrate microsatellite instability and abnormal immunohistochemical staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep;63:749-59; Otway R et al. Hum. Mutat. 2000;16:61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Chubb D et al. J. Clin. Oncol., 2015 Feb;33:426-32; Grant RC et al. Gastroenterology, 2015 Mar;148:556-64; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). Alterations at this codon are predicted to lead to a protein with an N-terminal truncation of 25 amino acids due to the presence of another methionine codon 76 nucleotides downstream of the original start codon. Studies of this truncated MSH2 protein reflect an impaired ability to bind and cleave ATP, although it retains its ability to heterodimerize with MSH6 and MSH3 and it can still bind to mismatched DNA, albeit at a reduced rate (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). Transfection of a cDNA containing the c.1A>C alteration into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in repair of an exogenous mismatched protein. This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). These functional data support the reported phenotype of two siblings who are compound heterozygous for an MSH2 start codon alteration and an MSH2 gross deletion who do not have Constitutional Mismatch Repair Deficiency (CMMRD) but who have an unusually severe Lynch tumor burden (Kets CM et al. Eur. J. Hum. Genet. 2009 Feb;17:159-64). This alteration has also been seen in a compound heterozygous state with an MSH2 truncation mutation in an individual who reportedly did not have features of CMMRD (Rosenthal ET et al. Clin. Genet. 2015 Dec;88:533-41). This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000409939 SCV000487978 uncertain significance Lynch syndrome I 2015-12-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656870 SCV000601448 uncertain significance not provided 2019-10-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160588 SCV000902903 likely benign Hereditary cancer-predisposing syndrome 2015-03-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505793 SCV001370668 uncertain significance not specified 2020-05-16 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream methionine codon located 26 residues into the protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 214958 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome), allowing no conclusion about variant significance. c.1A>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Otway_2000), MSI low sigmoid colon tumor who did not fulfill both the modified Amsterdam and Bethesda criteria (Barnetson_2006 and 2008), Ovarian cancer who did not meet the Bethesda criteria for HNPCC (Cyr_2012), epithelial ovarian cancer (Pal_2012), colorectal cancer (Rosenthal_2015, DeRycke_2017), breast cancer (Desmond_2015) and diffuse gastric cancer (Fewings_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Co-occurrences in trans with other pathogenic variant(s) have been reported in patients with no evidence of constitutional mismatch repair deficiency (CMMRD) (MSH2 exons 1-6del and MSH2 c.2038C>T, p.Arg680* in Rosenthal_2015). This provides supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity using a lentiviral expression system to study mismatch repair (Cyr_2012). Six clinical diagnostic laboratories and one expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; Likely benign, n=1). Some of the submitters have provided overlapping evidence utilized in the context of this evaluation. Based on the published evidence spanning 12 years (2008-2018) as outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358333 SCV001554037 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH2 p.Met1? variant was identified in 5 of 8838 proband chromosomes (frequency: 0.001) from individuals or families with ovarian, colorectal, or pancreatic cancer and was not identified in 2844 control chromosomes from healthy individuals (Barnetson 2008, DeRycke 2017, Grant 2015, Otway 2000, Pal 2012). The variant was also identified in dbSNP (ID: rs267607911) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight, Invitae, GeneDx, Ambry Genetics, Counsyl and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, UMD-LSDB (1x as causal), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors (2x uncertain significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or Zhejiang University databases. The variant was identified in control databases in 11 of 208952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant observed in European population in 11 of 93132 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1A>C p.Met1? variant occurs in the first base of the translation initiation site (the Methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. In addition, 1 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. An in vivo MMR assay by Cyr (2012) suggests the variant may have a moderate impact on disease phenotype. This alteration leads to the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. Production of functional protein occurs through use of an alternative start codon at codon 26. In addition, the later study by Rosenthal (2015) published the case of two siblings with this variant in trans with a deletion of exons 1–6 in MSH2, and no reported features of CMMR-D, and in trans with the pathogenic variant MSH2 c.2038C>T (p.Arg680*) in patient without reported features of CMMR-D. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.