Submissions for variant NM_000249.3(MLH1):c.109G>A (p.Glu37Lys) (rs63751012)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000693918	SCV000822341	uncertain significance	Hereditary nonpolyposis colon cancer	2018-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 37 of the MLH1 protein (p.Glu37Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with suspected Lynch syndrome, endometrial cancer, or ovarian cancer (PMID: 12624141, 18415027, 27435373). ClinVar contains an entry for this variant (Variation ID: 89640). Experimental studies have shown that this missense change results in a mislocalized protein with decreased binding to PMS2 and decreased the DNA mismatch repair activity in vitro (PMID: 22753075, 20020535). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075110	SCV000887392	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.109G>A has a 99.97% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

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