Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

Rashid, Muhammad Usman; Naeemi, Humaira; Muhammad, Noor; Loya, Asif; Lubiński, Jan; Jakubowska, Anna; Yusuf, Muhammed Aasim

doi:10.1186/s13053-019-0128-2

Hereditary Cancer in Clinical Practice

Table 4 Characteristics of the families with pathogenic/likely pathogenic MLH1/MSH2 variants

From: Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

Study Id	Nucleotide change	Gender	Age at onset	Tumor location	Family history (age at onset in years)	Criteria	LOVD^a	Ethnicity
Families with MLH1 variants
C162	c.1672G > T	F	32	Transverse colon	CRC (32, 45, 45,?,?), BC (42, > 45), unknown (?)	HNPCC	P	Kashmiri
C92	c.2041G > A	M	41	Transverse colon	CRC (42)	suspected-HNPCC	P	Punjabi
C122	c.2041G > A	M	41	Rectum	Brain tumor (16)	non-HNPCC		Urdu speaking
C203	c.1358dup	F	44	Sigmoid colon	CRC (< 30, 35, 54, 62), abdomen (?), stomach (36)	HNPCC	P	Punjabi
C202	c.67delG	F	48	Cecum	CRC (38, 42, 45)	HNPCC	P	Pathan
H707	c.1358dup	M	61	Transverse colon	CRC (31, 35, 45, 45, < 50, 50, 61,?)	HNPCC	P	Punjabi
Families with MSH2 variants
C143	c.943-1G > C	M	32	Rectosigmoid	CRC (40, 59, 60)	HNPCC	LP	Pathan
C164	c.1786_1788delAAT	M	39	Ascending colon	BC (50)	non-HNPCC	P	Punjabi
H1075	c.943-1G > C	M	43	Ascending colon	CRC (55), unknown (< 21,?)	suspected-HNPCC		Pathan
C85	c.1861C > T	M	45	Rectum	CRC (65)	suspected-HNPCC	P	Punjabi
H421	c.2656G > T	F	48, 67	Endometrium, breast	CRC (43, 55, 59), BC (58, 60, 66/76, 67), OC (43, 51, 57), ALL (5), endometrium (46, 52, 53), intestine (42, 45), stomach (59), liver (60), prostate (58), renal (58), brain (13), osteosarcoma (13)	suspected-HNPCC	P	Pathan
C49	c.943-1G > C	M	60	Sigmoid colon	CRC (50)	suspected-HNPCC		Pathan
Families with novel MLH1/MSH2 variants
C141	c.116 + 3A > T^b	M	30	Sigmoid colon	–	non-HNPCC	NR/LP^b	Punjabi
C199	c.2120G > A^c	M	38	Rectum	CRC (40, 45, 50, 52, 65,?,?)	HNPCC	NR/LP^c	Pathan
C75	c.2120G > A^c	F	38	Recto sigmoid	Brain tumor (?)	non-HNPCC		Punjabi
P53	c.2120G > A^c	F	54	Rectum	–	non-HNPCC		Punjabi
Families with a previously reported MLH1 variant
C198	c.1919C > T	M	35	Transverse colon	CRC (25, 30, 43, 66,?)	HNPCC	VUS/LP^d	Pathan
C199	c.1919C > T	M	38	Rectum	CRC (40, 45, 50, 52, 65,?,?)	HNPCC		Pathan
C72	c.1919C > T	F	38	Transverse colon	Bladder (50), Bone (50)	suspected-HNPCC		Pathan
C55	c.1919C > T	M	38	Cecum	CRC (60)	suspected-HNPCC		Pathan
P02	c.1919C > T	M	45	Transverse colon	CRC (?,?,?)	HNPCC		Pathan
H708	c.1919C > T	M	51	Ascending colon	CRC (50, 65)	suspected-HNPCC		Pathan
P01	c.1919C > T	M	52	Transverse colon	CRC (?,?), Endometrium (?), Spleen (?)	non-HNPCC		Pathan
C185	c.1919C > T	F	60	Colon	Stomach (15), Epithilial (18)	non-HNPCC		Pathan

?, age at diagnosis is not known
ALL Acute lymphoid leukemia, BC Breast cancer, CRC Colorectal cancer, LP Likely pathogenic, NR No record in LOVD database, OC ovarian cancer, P pathogenic, VUS variant of uncertain significance
^aClassification is based on Leiden Open Variation Database (LOVD) maintained by International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
^bThis variant is considered as likely pathogenic by four of the five splice-site prediction algorithms
^cThis variant is considered as likely pathogenic by five of the seven protein function prediction algorithms
^dThis variant is reported as VUS in LOVD database and considered in the current study as likely pathogenic by seven of the seven protein function prediction algorithms combined with functional assay [29]

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ISSN: 1897-4287

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