Submissions for variant NM_000251.3(MSH2):c.1865C>T (p.Pro622Leu)

dbSNP: rs28929483

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076307	SCV000107329	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000566777	SCV000669704	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-04	criteria provided, single submitter	clinical testing	The p.P622L pathogenic mutation (also known as c.1865C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1865. The proline at codon 622 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in numerous individuals meeting Amsterdam I/II criteria with absence of MSH2 and/or MSH6 on immunohistochemistry, and/or microsatellite unstable tumors (Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Schofield L et al. Int. J. Cancer 2009 Mar;124:1097-102; Arnold S et al. Hum. Mutat., 2009 May;30:757-70; Rosty C et al. Fam. Cancer 2014 Dec;13:573-82). Also, numerous studies in mammalian and yeast systems have demonstrated that this alteration results in reduced mismatch repair activity (Gammie AE et al. Genetics 2007 Oct;177:707-21; Lützen A et al. Mutat. Res. 2008 Oct;645:44-55; Mastrocola AS et al. Hum. Mutat. 2010 Oct;31:E1699-708; Wielders EA et al. Hum. Mutat. 2011 Apr;32:389-96; Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). In the literature, this variant co-segregated with disease in 30 of 30 affected members in 2 families (Leach FS et al. Cell 1993 Dec;75:1215-25; Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Arnold S et al. Hum. Mutat. 2009 May;30:757-70). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000630204	SCV000751160	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MSH2 function (PMID: 12124176, 17720936, 18822302, 19267393, 21309037, 22102614, 22949379, 24362816). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 1753). This variant is also known as 1933C>_x0001_T (P622L). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 8261515, 16616355, 22283331, 25117503). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 622 of the MSH2 protein (p.Pro622Leu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076307	SCV000917690	pathogenic	Lynch syndrome	2017-11-03	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1865C>T (p.Pro622Leu) variant involves the alteration of a conserved nucleotide located in the DNA mismatch repair protein MutS, core domain (IPR007696) (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A yeast functional study showed 4% MMR activity associated with this variant (Gammie_2007). This variant is absent in 246248 control chromosomes in gnomAD. This variant was reported in multiple patients with LS and it showed perfect segregation with disease in affected families (Arnold_2009, Leach_1993). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx	RCV002460877	SCV002757350	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced protein expression, deficient ATP binding, abnormal cellular localization, and impaired MMR activity (Drotschmann et al., 1999; Fishel et al., 2000; Heinen et al., 2002; Belvederesi et al., 2008; Lutzen et al., 2008; Mastrocola et al., 2010; Rath et al., 2019; Jia et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16426447, 26951660, 11048710, 16804905, 21309037, 18383312, 31773066, 25117503, 17594722, 22949379, 22949387, 24362816, 19267393, 18822302, 9774676, 17426132, 22833534, 9630599, 22824075, 12385013, 22322191, 14518068, 12760035, 27035997, 8261515, 8062247, 16616355, 10469597, 22102614, 20672385, 12124176, 17192056, 11555625, 18781619, 17720936, 7717919, 28125613, 8484120, 31237724, 19072991, 33357406, 28422960, 28785832, 29967423, 19766128, 33119594, 31569399, 16116158, 21120944)
OMIM	RCV000001823	SCV000021979	pathogenic	Lynch syndrome 1	1993-12-17	no assertion criteria provided	literature only