Submissions for variant NM_000251.3(MSH2):c.965G>A (p.Gly322Asp)

gnomAD frequency: 0.01714  dbSNP: rs4987188

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030257	SCV000107802	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1% & Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV001083998	SCV000153907	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121567	SCV000170332	benign	not specified	2013-09-27	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	RCV000157760	SCV000212730	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Vantari Genetics	RCV000157760	SCV000267049	benign	Hereditary cancer-predisposing syndrome	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000157760	SCV000292106	benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000030257	SCV000296897	benign	Lynch syndrome	2015-11-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121567	SCV000303167	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000144615	SCV000430919	likely benign	Lynch syndrome 1	2018-03-06	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034561	SCV000604258	benign	not provided	2023-11-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000144615	SCV000743208	benign	Lynch syndrome 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000144615	SCV000744271	benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000144615	SCV000745635	benign	Lynch syndrome 1	2015-08-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262750	SCV001440732	likely benign	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000157760	SCV002526782	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121567	SCV002552214	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000157760	SCV002819171	benign	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000144615	SCV004015940	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
OMIM	RCV000001832	SCV000021988	benign	MSH2 POLYMORPHISM	1998-11-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034561	SCV000043338	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030257	SCV000052924	benign	Lynch syndrome	2015-04-08	no assertion criteria provided	clinical testing
ITMI	RCV000121567	SCV000085762	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144615	SCV000189942	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000121567	SCV000257200	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353916	SCV000592482	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Gly322Asp variant has been identified in 78 out of 3532 proband chromosomes (frequency 0.022) in individuals with endometrial and colorectal cancer phenotypes, however it is also found in 69 out of 2790 control chromosomes (frequency 0.025), increasing the likelihood that this is a benign variant (Barneston 2008, Christensen 2008, Aceto 2009, Hampel 2006, Kurzawski 2006, Raptis 2005, Valentin 2011, Pastrello 2011, Sven Arnold_2009). It is listed in dbSNP database (ID#: rs4987188) with an average heterozygosity of 0.019+/-0.096 in various human populations, further suggesting the benign nature of this variant. The p.Gly322 is highly conserved in mammals and other species, however in silico computational analysis (Sift, PolyPhen and AlignGVGD) do not suggest an impact on the protein function, therefore increasing the likelihood of this variant to be benign. Although functional impact for the yeast homolog (yMSH2–G317D) have been suggeested by earlier yeast assays (Drotschmann 1999; Ellison 2001), recent studies did not implicate any functional impact associated with the p.Gly322Asp variant (Wielders 2011, Kansikas 2011, Ollila 2008). In summary, based on the above information this variant is classified as Benign.
True Health Diagnostics	RCV000157760	SCV000788040	benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121567	SCV001797363	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121567	SCV001906032	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121567	SCV001919760	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121567	SCV001956602	benign	not specified		no assertion criteria provided	clinical testing