Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain

Table 1 Classification of colorectal cancer families, frequencies of pathogenic mutations in hMLH1 and hMSH2 genes and MSI phenotype

Clinical criteria	Number of families	hMLH1 mutations	MSH2 mutations	MSI-H	MSS	MSI untyped
Amsterdam I	56	17	15	42	13	1
Amsterdam II	11	2	2	2	7	2
Bethesda	37	5	0	6	20	11
HNPCC-like	38	0	0	3	20	5
Total	132	24	17	53	60	19

Table 2 hMSH6 mutations in Spanish HNPCC families

Family	Clinicalcriteria	Dx agedindex patient (y)	No. of tumorsin the family	Exon/intron	Nucleotidechange	Amino acidchange	Predictedconsequence	Nfdhtdata base
3	Bethesda	42	1E, 1G, 1M, 1H, 1F, and 1A	Ex. 8	c.3725 G > T	R1242L	Inconclusive	No
11	HNPCC-like	58	1G, 2C, and 1B	Ex. 4	c.2319 C > T	L773L	Inconclusive	No
68	Bethesda	29	1L, and 1C	Ex. 4	c.1164 C > T	H388H	Inconclusive	No
				Ex. 4	c.2272 C>T	L758L
81	HNPCC-like	50	4C	Int. 5	c.3439?6 C > T	NA	Inconclusive	No
94	Amsterdam II	45	3 P, 2E, 1G, and 3C	Ex. 4	c.2633 T > C	V878A	Pathogenic	Yes
100	Amsterdam II	54	4C, 1P, and 3G	Ex. 4	c.706 C > T	Q236X	Truncation	No
73	Amsterdam	29	2SM, 1G, 3C, and 1L	Ex. 4	c.2633 T > C	V878A	Pathogenic	Yes
121	HNPCC-like	58	3C, 1G, and 1B	Int. 5	c.3439?6 C > T	NA	Inconclusive	No
138	Bethesda	43	2C and 1 ureter in the same patient	Ex. 4	c.1677 C > T	C559C	Inconclusive	No

E, endometrial; G, glioma; M, meningioma; H, hemangioma; F, fibrosarcoma; A, adenoma; G, gastric; C, colon; B, breast; L, larynx; P, prostate; B, brain; SM, small intestine; y, years.

Table 3 hMSH6 polymorphisms in Spanish HNPCC families

Location	Nucleotidechange	Aminoacid change	Previouslyreported	Frequency1
Exon 1	116 G→A	G 39 E	Yes	0.40
Exon 2	276 A→G	P 92 P	Yes	0.38
Exon 3	540 T→C	D 180 D	Yes	0.24
Exon 4	642 C→T	Y 214 Y	Yes	0.25

¹Patients harboring/patients screened.

Table 4 Molecular alterations of tumors from persons carrying mutations of hMSH6 gene

Family/member	Tumor type	MSI status	Immunohistochemistry			hMSH6 mutation	Other MMR gene mutation
			MLH1	MSH2	MSH6
3/270	CRC	MSI-H	P	P	P	R1242L	V716M (hMLH1)
11/310	CRC	MSI-H	P	P	P	L773L	NO
68/675	CRC	MSS	P	P	P	H388H and L758L	NO
73/526	3 CRCs	MSI-H	P	P	N	V878A	NO
81/757	CRC	MSS	P	P	P	c.3439?6 C > T	K618A (hMLH1)
94/854	UTERO	MSI-H	P	P	N	V878A	K618A (hMLH1)
100/940	CRC	MSS	P	P	N	Q236X	NO
121/1041	CRC	MSS	ND	ND	ND	c.3439?6 C > T	NO
138/1165	2 CRCs	MSI-H	P	P	P	C559C	P350P (hMLH1)

CRC, colorectal cancer; MSI-H, high microsatellite instability; MSS, negative microsatellite instability; P, positive for MMR protein; N, negative for MMR protein; ND, not done MMR expression.