Submissions for variant NM_000251.3(MSH2):c.1661G>C (p.Ser554Thr)

dbSNP: rs63750597

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076221	SCV000107239	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration (full inactivation of variant allele)
Ambry Genetics	RCV000491785	SCV000580424	pathogenic	Hereditary cancer-predisposing syndrome	2016-09-07	criteria provided, single submitter	clinical testing	The c.1661G>C pathogenic mutation (also known as p.S554T), located in coding exon 10 of the MSH2 gene, results from a G to C substitution at nucleotide position 1661. This change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. In addition, this alteration changes the serine at codon 554 to threonine, an amino acid with similar properties. This mutation was first described in a German patient meeting Amsterdam I criteria, who had rectal cancer at 59 years of age and whose tumor was absent for MSH2 on IHC and showed high microsatellite instability. Family history included a mother and brother with colon cancer at 43 and 31 years of age, respectively. RT-PCR analysis of mRNA revealed skipping of exon 10, which the authors concluded established the pathogenicity of this alteration (Kruger S et al. Hum Mutat. 2004;24(4):351-2). One study described another mutation at this nucleotide position (c.1661G>A), which was detected in a large Lynch syndrome family (44 individuals tested). The proband was diagnosed with cancer of the colon-rectum, rectum-sigma at 47 years of age, and his tumor was absent for MSH2/MSH6 and showed high microsatellite instability. Functional analysis showed that this mutation abolished the consensus splice donor site and resulted in the deletion of 81 bp in the mRNA (Perez-Cabornero L et al. Eur J Cancer. 2009 May;45(8):1485-93). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
Myriad Genetics, Inc.	RCV003452847	SCV004186650	likely pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15365996].
Invitae	RCV003593896	SCV004293890	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-05-19	criteria provided, single submitter	clinical testing	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in skipping of exon 10 (PMID: 15365996). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 90724). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 15365996). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 554 of the MSH2 protein (p.Ser554Thr). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357409	SCV001552876	uncertain significance	not provided		no assertion criteria provided	clinical testing