ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1A>G (p.Met1Val) (rs267607911)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076335 SCV000107359 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Insufficient evidence
Ambry Genetics RCV000165763 SCV000216508 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Pathway Genomics RCV000172811 SCV000223777 uncertain significance Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000235433 SCV000292892 uncertain significance not provided 2015-05-20 criteria provided, single submitter clinical testing The c.1A>G 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 was reported in two siblings who were compound heterozygotes for MSH2 c.1A>G and a known pathogenic MSH2 deletion in the absence of constitutional mismatch repair-deficiency (CMMR-D) syndrome, but who did display a phenotype more severe than classical Lynch syndrome, leading the authors to suggest that a variant in this start codon may be associated with reduced penetrance (Kets 2009). Additionally, the unaffected mother was found to only harbor the MSH2 c.1A>G variant, which in combination with the lack of Lynch syndrome-associated cancers in her family, further supports a less severe phenotype than classic Lynch syndrome. Corresponding tumor studies from the siblings showed weak MSH2 staining and microsatellite instability, suggesting that this variant confers reduced, but not complete, loss of protein activity. Another initiation codon variant, MSH2 c.1A>C, has also been suggested to be associated with an attenuated Lynch syndrome phenotype. This variant demonstrated impaired, but not complete loss of protein activity, and has been shown to produce multiple protein products, including both full-length and truncated MSH2 protein (Barnetson 2006, Barnetson 2008, Cyr 2012). Thus, the effects of these two start codon missense variants appear to be similar. There is some published evidence that this variant increases the risk of Lynch-related cancers (colon, endometrial, etc.) in the heterozygous state. However, based on internal data acquired from multiple observations of this variant and MSH2 c.1A>C 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>G are not well understood, thus we consider it to be a variant of uncertain significance.
Invitae RCV000560664 SCV000625336 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-07 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MSH2 mRNA. It is predicted to lead to a truncated protein as a result of alternate initiator methionine 25 codons downstream. This variant is present in population databases (rs267607911, ExAC 0.06%). This variant has been reported in an individual with pancreatic cancer, who also carried a pathogenic variant in the CDKN2A gene (PMID: 27449771). It has also been reported in trans with a pathogenic MSH2 variant in two siblings who did not present with constitutional mismatch repair deficiency syndrome, which suggests that this c.1A>G substitution in MSH2 was not the primary cause of disease in those individuals (PMID: 18781192). ClinVar contains an entry for this variant (Variation ID: 90833). Analysis of patient tumor and normal tissue showed that this variant does not lead to loss of MSH2 protein expression (PMID: 18781192). Different variants in the MSH2 initiator codon, c.1A>C and c.1A>T, have been shown to lead to expression of a protein lacking the first 25 amino acid residues (PMID: 21837758, 9718327). 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, this is a rare sequence change at the initiator codon that likely results in a truncated protein with slightly reduced activity. In the absence of additional functional and/or genetic data, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000076335 SCV000837809 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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