Submissions for variant NM_000251.3(MSH2):c.984C>T (p.Ala328=)

gnomAD frequency: 0.00495  dbSNP: rs4987189

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076774	SCV000107813	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV000192476	SCV000170333	benign	not specified	2014-01-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000126809	SCV000212787	likely benign	Hereditary cancer-predisposing syndrome	2014-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000192476	SCV000248075	benign	not specified	2019-02-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079823	SCV000252657	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000192476	SCV000303168	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000613302	SCV000430920	likely benign	Lynch syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000126809	SCV000685147	benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000613302	SCV000744272	likely benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656570	SCV001158687	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000192476	SCV002552215	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000613302	SCV004015951	likely benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126809	SCV004228083	benign	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656570	SCV005263953	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000192476	SCV000592483	benign	not specified		no assertion criteria provided	clinical testing	The MSH2 p.Ala328= variant was identified in 8 of 1632 proband chromosomes (frequency: 0.005) from Italian, Dutch, Australian and Chinese individuals or families suspected of having Lynch syndrome/meeting Amsterdam and/or Bethesda criteria, and was identified in 1 of 346 control chromosomes (frequency: 0.003) from healthy individuals (Pastrello_2011_21239990, Yap_2009_18726168, Curia_1999_10446963, Lee_2005_15996210, Scott_2001_11112663, Overbeek_2007_17453009, Samowitz_2001_11606497). The variant was also identified as a somatic mutation in a study of sporadic colon tumors of Hungarian patients (Kamory 2003). In 1 proband with an MSI+/ hypermethylation negative, IHC intact tumour, germline analysis identified the variant co-occurring with an unclassified variant c.250A4G (p.Lys84Glu) in MLH1 (Overbeek_2007_17453009), and in another study with a pathogenic MSH2 variant (c.942+2T>A) (Pastrello_2011_21239990). The variant was identified in the following databases: dbSNP (ID: rs4987189) “With Likely benign, other allele”, ClinVar (classified likely benign, reviewed by an expert panel (2013); submitters: benign by GeneDx, Invitae and Prevention Genetics, and likely benign by InSIGHT, Ambry Genetics, and Illumina), Clinvitae (3x), Cosmic (1x in a carcinoma of the large intestine), UMD-LSDB (6x as neutral, co-occurring with pathogenic variants MSH6 (c.2455G>T/p.Glu819X), and MLH1 (c.1489delC/ p.Arg497GlyfsX11, c.121G>C/p.Asp41His), Insight Colon Cancer Gene Variant Database (16x as class 2), Mismatch Repair Genes Variant Database (8x), Insight Hereditary Tumors Database (18x), and in control databases in 1270 (26 homozygous) of 277190 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 22 of 6468 chromosomes (freq: 0.003), Latino in 95 (1 homozygous) of 34416 chromosomes (freq: 0.003), European Non-Finnish in 212 of 126682 chromosomes (freq: 0.002), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 5 of 25786 chromosomes (freq: 0.0002), and South Asian in 926 (25 homozygous) of 30782 chromosomes (freq: 0.03). The variant was not identified in GeneInsight-COGR, MutDB, or Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 4 individuals with colon cancer. 1 pos case variant cooccurred with pathogenic msh2 mutation c.942+2T>Apos case malyasianunrelated healthy controls. The p.Ala328= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000613302	SCV000734198	likely benign	Lynch syndrome 1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000613302	SCV000745636	likely benign	Lynch syndrome 1	2015-08-21	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656570	SCV000778617	likely benign	not provided	2017-12-18	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000126809	SCV000805271	likely benign	Hereditary cancer-predisposing syndrome	2018-05-29	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000192476	SCV001918443	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000192476	SCV002034119	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000192476	SCV002036625	benign	not specified		no assertion criteria provided	clinical testing