Submissions for variant NM_000251.3(MSH2):c.1807G>A (p.Asp603Asn)

dbSNP: rs63750657

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076291	SCV000107312	uncertain significance	Lynch syndrome	2018-03-09	reviewed by expert panel	curation	Insufficient evidence
Color Diagnostics, LLC DBA Color Health	RCV000774575	SCV000908317	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 603 in the MSH3/MSH6 interaction domain of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mismatch repair activity in yeast and mammalian cell-based assays (PMID: 17101317, 17720936, 26951660). This is a recurrent variant in the Finnish population and has been reported in several Finnish families affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 10829038, 15837969, 17043646, 17101317, 17267619, 23544471). Microsatellite instability has been demonstrated in multiple tumor samples from these individuals (PMID: 15837969, 17101317, 17267619). Immunohistochemistry has demonstrated loss of MSH2 protein expression in multiple tumor samples (PMID: 15837969, 17101317). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001253791	SCV001429662	likely pathogenic	Hereditary nonpolyposis colon cancer	2018-11-09	criteria provided, single submitter	clinical testing	Data used in classification: Absent from gnomAD (PM2_mod). Functional evidence that this variant disrupts MMR activity and protein expression: (1) Kansikas et al 2010 (PMID: 21120944) found that this variant resulted in loss of MSH2 (and MSH6) expression and disruption of MMR function (2); Gammie et al 2007 (PMID: 17720936) showed in Saccharomyces cerevisiae that this variant resulted in low levels of MSH2 expression (5% of WT protein level) and lost subunit interactions based on yeast two-hybrid assay. (PS3_mod). In silico predictions predict this as deleterious across multiple tools (SIFT, Polyphen2, MutationTaster). (PP3_sup). MSH2 c.1808A>G p.Asp603Gly Class 4 on INSIGHT, less conservative than current variant (PM5_sup). UK family 1: Tumour studies showing MSI and loss of MSH1 and MSH6 protein expression in the proband with caecal adenocarcinoma (age 51) with this variant. (PP4_sup). Additional Information (not included in classification): Four Finnish Lynch syndrome families in literature shown to have this variant with evidence of segregation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358217	SCV001553891	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Asp603Asn variant was identified in 3 of 2108 proband chromosomes (frequency: 0.001) from individuals or families with endometrial and colorectal cancer (Ollikainen 2005, Salovaara 2000). The variant was identified dbSNP (rs63750657) as “with uncertain significance allele”, in ClinVar (classified as likely pathogenic by Color and as uncertain significance by InSiGHT expert panel in 2013). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant was identified in a patient with two primary, MSH2- and MSH6-deficient, Lynch-related tumours (endometrial and ovarian; Ollikainen 2005). Functional studies on this variant have demonstrated a complete loss of MMR activity, reduction of MSH2 protein expression on a Western blot, lower levels of protein stability, and slippage rates similar to a partially pathogenic control (Ollila 2006, Ollila 2008, Houlleberghs 2016). The p.Asp 603Asn variant is located in the region that interacts with EXO1, MSH3 and MSH6, which could hinder these protein-protein interactions (Houlleberghs 2016). The p.Asp603 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.