Submissions for variant NM_000251.3(MSH2):c.815C>T (p.Ala272Val)

gnomAD frequency: 0.00046  dbSNP: rs34136999

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076728	SCV000107764	benign	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000034559	SCV000149451	likely benign	not provided	2020-09-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21120944, 22102614, 16995940, 27449771, 29371908, 10080150, 22949387, 18951462, 17101317, 19690142, 15872200, 20587412, 18561205, 11606497, 18566915, 25637381, 17594722, 22703879, 26951660, 25569433, 27328445, 10422993, 32741062)
Invitae	RCV001081902	SCV000166286	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115542	SCV000172868	likely benign	Hereditary cancer-predisposing syndrome	2018-06-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000212591	SCV000595835	uncertain significance	not specified	2017-03-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034559	SCV000601490	likely benign	not provided	2023-06-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115542	SCV000690134	likely benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212591	SCV000696286	benign	not specified	2021-06-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.815C>T (p.Ala272Val) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 252008 control chromosomes, predominantly at a frequency of 0.00041 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is close to that estimated for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00041 vs 0.00057), supporting a benign role for the variant of interest. c.815C>T has been reported in the literature in individuals affected with Lynch Syndrome, as well as colorectal-, pancreatic-, breast- and skin cancers (example, Lin_1999, Ollila_2006, Nilbert_2009, Samowitz_2001, Syngal_1999, Yang_2016, Dominguez-Valentin_2018, Cho_2018, Young_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. <ultiple co-occurrences with other pathogenic variants have been reported (MSH2 c.518T>G / p.Leu173Arg, in the UMD database; MLH1 del exon 6, Mueller_2009; BRCA2 c.9382C>T / p.Arg3128X, Domingues-Valentin_2018), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating the impact of MSH2 c.815C>T on protein function. The variant was shown to mildly affect the normal splicing pattern by causing exon 5 exclusion (Tournier_2008, Lastella_2006, Dominguez-Valentin_2018), however tumors in mutation carriers showed normal MSH2 expression (Ollila_2006). In addition, the variant was shown to be MMR-proficient by the in vitro MMR assay as reported by several independent research groups (Ollila_2006, Ollila_2008, Drost_2011). Taken together these results indicate that this variant does not significantly damage MSH2 protein function. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments with the expert panel and five other submitters reporting a benign/likely benign outcome. Based on the absence of evidence supporting an actionable outcome in literature spanning over two decades of evolution as outlined above, the variant was re-classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212591	SCV000711973	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala272Val variant in MSH2 has been reported in at least 11 individuals with Lynch Syndrome-related cancers (Ollila 2006, Mueller 2009, InSiGHT database (http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php)). One of these patients carried a second pathogenic variant in MLH1. In vitro functional studies provide some evidence that the p.Ala272Val variant may have a slight impact on the protein (Tournier 2008, Lastella 2006), however others demonstrate an effect comparable to that in the wild-type (Ollila 2006). These types of assays may not accurately represent biological function. This variant has been identified in 11/10358 Ashkenazi Jewish chromosomes (0.1%) by the Genome Aggregation Consortium (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addition, it has been classified as Uncertain Significance on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107764.2). In summary, the clinical significance of the p.Ala272Val variant is uncertain.
Counsyl	RCV000663110	SCV000786235	uncertain significance	Lynch syndrome 1	2018-03-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891467	SCV000806049	likely benign	MSH2-related condition	2020-12-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mendelics	RCV000663110	SCV001135708	benign	Lynch syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115542	SCV002526749	benign	Hereditary cancer-predisposing syndrome	2020-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212591	SCV002552204	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149609	SCV003838297	likely benign	Breast and/or ovarian cancer	2022-12-23	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115542	SCV004014897	likely benign	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663110	SCV004018426	benign	Lynch syndrome 1	2023-03-24	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034559	SCV000043336	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148632	SCV000190347	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357272	SCV001552691	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Ala272Val variant was identified in 1 of 1132 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Hampel 2005). The variant was also identified in dbSNP (ID: rs34136999) as “With other allele”, in ClinVar (classified as benign by Invitae; likely benign by GeneDx, Ambry Genetics, color Genomics; uncertain significance by 5 clinical laboratories), Clinvitae (conflicting interpretations of pathogenicity), MutDB, UMD-LSDB (classified as neutral), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.518T>G, p.Leu173Arg), increasing the likelihood that the p.Ala272Val variant does not have clinical significance. The variant was not identified in GeneInsight-COGR, Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 77 of 276232 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 23984 chromosomes (freq: 0.0001), Other in 2 of 6438 chromosomes (freq: 0.0003), Latino in 14 of 34346 chromosomes (freq: 0.0004), European Non-Finnish in 49 of 126334 chromosomes (freq: 0.0004), Ashkenazi Jewish in 9 of 10140 chromosomes (freq: 0.001), and South Asian in 1 of 30510 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, European Finnish, populations. Several functional studies demonstrated this variant resulted in partial exon 5 skipping (Lastella 2006, Tournier 2008) and slightly reduced mismatch binding of the MMR reaction (Ollila 2008). The variant showed no reduction in mismatch repair capability compared with the wild-type MSH2 (Ollila 2006). In addition, the variant was identified with a pathogenic BRCA2 c.9382C>T in a patient diagnosed with ductal carcinoma at 44 years of age (Dominguez-Valentin 2018). The p.Ala272 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 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 benign role for this variant. This variant is classified as likely benign.