Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2genes in yeast

BMC Cancer

Table 1 Comparison of published functional and clinical data on hMLH1 variants

MLH1 alteration	Functional and biochemical assays		Clinical data
	Assay type	Outcome^a	MSI^b	MLH1 IHC^c	Age^d	Family history/segregation	Ref.
A92P^e							[30]
S93G	In vivo MMR assay [11, 10]	- -			70	YES/	[9]
	In vitro MMR assay [11, 9, 3]	- - -	YES	POS	90	YES/	[32]
	In vitro protein interaction assay [9, 3]	- -	YES	NEG	53	YES/	[32]
	MLH1 expression/localization [11, 9]	- -					[33]
					65	YES/YES	[3]
T117M^e	In vivo MMR assay [11, 13]	+ +	YES				[34]
	In vitro MMR assay [11, 12]	+ +			40	YES/	[35]
	In vivo protein interaction assay [7]	+	YES	NEG	43	YES/	[36]
	In vitro protein interaction assay [7, 12]	± ±	NO	POS	42	YES/	[36]
	MLH1 expression/localization [11, 7, 13, 16]	+ + + +	YES			YES/	[37]
			YES	POS	55	YES/	[38]
			YES	NEG			[39]
I219V	In vivo MMR assay [11, 13]	- -		POS	55		[36]
	In vitro MMR assay [11, 9, 12]	- - -
	In vivo protein interaction assay [7]	-
	In vitro protein interaction assay [9, 12]	- -
	MLH1 expression/localization [11, 9]	± -
K618R^e			YES	NEG			[40]
					< 50	NO/	[41]
K618T^e	In vivo MMR assay [11, 13]	+ +	NO	POS		YES/NO	[43]
	In vitro MMR assay [11, 9]	± -	NO	POS		YES/NO	[44]
	In vivo protein interaction assay [7]	-			42	NO/	[45]
	In vitro protein interaction assay [7, 42, 9, 12]	+ + - +
	MLH1 expression/localization [11, 7, 13, 9]	± ± ± ±
Y646C	In vitro MMR assay [9]	-	YES	NEG	48	YES/	[46]
	In vitro protein interaction assay [9, 6]	- +	YES	NEG^f	36	YES/	[9, 47]
	MLH1 expression/localization [9, 6]	- -	YES	NEG	48	YES/	[6]
			YES	NEG	51	YES/	[6]
R659Q^e	In vivo MMR assay [11]	±	YES	NEG	32	YES/	[9]
	In vitro MMR assay [11, 9]	- -
	In vitro protein interaction assay [9]	-
	MLH1 expression/localization [11, 9]	± -

^aThe outcome of each assay is given: +, pathogenic; -, non-pathogenic; ±, inconclusive. Each symbol refers to the assay referenced in section: Assay type.
^bMicrosatellite instability.
^cImmunohistochemical staining of MLH1: POS, positive; NEG, negative.
^dPatients' age at cancer onset.
^eThe variant was also found in patients carrying a second MMR alteration. Those patients were excluded from the Table.
^fImmunohistochemical staining of PMS2. In this case MLH1 staining was positive.

ISSN: 1471-2407