ClinVar Miner

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

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Total submissions: 8
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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 colon cancer 2019-12-22 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, and colorectal cancers (PMID: 21837758, 23047549, 18033691, 10874307, 25479140, 28944238, 26270727). 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 2018-11-05 criteria provided, single submitter clinical testing The c.1A>C variant in the MSH2 gene results in the loss of the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant has been reported in individuals with colorectal or ovarian cancer and was absent from healthy controls (Otway 2000, Parc 2003, Barnetson 2006, Barnetson 2008, Pal 2012, Cyr 2012). MSH2 c.1A>C was observed at an allele frequency of 0.011% (11/93,132) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant has been shown to produce multiple protein products, including both full-length and truncated MSH2 protein (Cyr 2012). It has been recognized that CTG can sometimes be used instead of ATG as a weak initiation codon, thus allowing for translation (Cyr 2012). While some functional studies have demonstrated impaired DNA binding and mismatch repair activity, tumor studies have shown microsatellite stability (MSS) or low levels of instability (MSI-L), no loss of MSH2 protein expression, and no effect on MSH6 or MSH3 interaction, suggesting that this variant may be associated with an attenuated phenotype (Barnetson 2006, Barnetson 2008, Cyr 2012, DeRycke 2017). MSH2 c.1A>C and another initiation codon variant, MSH2 c.1A>G, have both been reported in trans with a known pathogenic MSH2 variant in individuals who did not have constitutional mismatch repair-deficiency (CMMR-D) syndrome (Kets 2009, Rosenthal 2015). Kets et al. (2009) reported a phenotype more severe than classical Lynch syndrome in two siblings who were compound heterozygotes for MSH2 c.1A>G and a known pathogenic MSH2 variant, leading the authors to suggest that variants impacting this start codon may be associated with reduced penetrance. Additionally, corresponding tumor studies from the siblings showed weak MSH2 staining and low levels of microsatellite instability, suggesting that this variant confers reduced, but not complete loss of protein activity, similar to the effect of MSH2 c.1A>C. In summary, there is some published evidence that MSH2 c.1A>C increases the risk of Lynch-related cancers (colon, endometrial, etc.) when present in the heterozygous state. However, based on internal data acquired from multiple observations of this variant in individuals without histories suggestive of Lynch syndrome, the cancer risks associated with this variant may be lower than what is expected for typical Lynch syndrome. Based on currently available data, the cancer risks associated with MSH2 c.1A>C are not well understood, thus we consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160588 SCV000214177 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-08 criteria provided, single submitter clinical testing Conflicting evidence
Counsyl RCV000409939 SCV000487978 uncertain significance Lynch syndrome I 2015-12-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505793 SCV000601448 uncertain significance not specified 2017-06-15 criteria provided, single submitter clinical testing
Color RCV000160588 SCV000902903 likely benign Hereditary cancer-predisposing syndrome 2015-03-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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