Submissions for variant NM_000251.2(MSH2):c.2064G>A (p.Met688Ile) (rs63750790)

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Total submissions: 8

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165796	SCV000216543	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-25	criteria provided, single submitter	clinical testing	Insufficient evidence
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center	RCV000410248	SCV000267401	uncertain significance	Lynch syndrome I	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000410248	SCV000488061	uncertain significance	Lynch syndrome I	2015-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000524376	SCV000548225	uncertain significance	Hereditary nonpolyposis colon cancer	2019-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with isoleucine at codon 688 of the MSH2 protein (p.Met688Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs63750790, ExAC 0.06%). This variant has been reported in individuals affected with colorectal and endometrial cancer, as well as in individuals with hereditary nonpolyposis colorectal cancer (PMID: 9559627, 10777691, 14499697, 23741719). It has also been observed in three control individuals in a healthy cohort of 179 individuals (PMID: 15527911). ClinVar contains an entry for this variant (Variation ID: 90875). Functional studies do not agree on the effect of this variant on mismatch repair activity (PMID: 17720936, 22739024, 21309037). A different missense substitution at this codon (p.Met688Arg) has been determined to be pathogenic (PMID: 22739024, 10080150, 15075785, 20010080, 22739024, 21239990, 21225464). This suggests that the methionine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Color	RCV000165796	SCV000685006	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000410248	SCV001135750	uncertain significance	Lynch syndrome I	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research	RCV001030713	SCV001193635	uncertain significance	Hereditary breast and ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Clinical Services Laboratory,Illumina	RCV000410248	SCV001300493	uncertain significance	Lynch syndrome I	2017-06-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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