Submissions for variant NM_000251.3(MSH2):c.1787A>G (p.Asn596Ser)

gnomAD frequency: 0.00022  dbSNP: rs41295288

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200985	SCV000149420	likely benign	not specified	2018-01-02	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081309	SCV000153982	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115511	SCV000187001	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034554	SCV000780663	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BS3:Supporting, BS1
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659882	SCV000781774	uncertain significance	Lynch syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034554	SCV000806012	likely benign	not provided	2017-10-27	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115511	SCV000822048	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765668	SCV000897010	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115511	SCV000902601	benign	Hereditary cancer-predisposing syndrome	2015-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200985	SCV000917713	benign	not specified	2025-01-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1787A>G (p.Asn596Ser) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 332158 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database v2.1 dataset. This frequency is somewhat lower than the estimated maximum for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057). However, the variant was reported with a higher allele frequency in the Middle Eastern subpopulation (i.e. 53/6062 alleles; AF: 0.0087), including 1 homozygote, in the gnomAD database v4.1 dataset, suggesting that it is likely a benign polymorphism. The variant, c.1787A>G, has been reported in the literature in individuals affected with tumors belonging to the Lynch syndrome spectrum, and with other tumor phenotypes (e.g. Mangold_2005, Woods_2005, Betz_2010, Maxwell_2015, Raskin_2017, Damaso_2020, Dorling_2021, Fonfria_2021), as well as in controls (e.g. Dorling_2021). A family with this variant suggests lack of segregation with the disease since one of the affected family members did not carry the variant, although four affected family members did carry the variant (Genuardi_1999). One publication indicates the variant co-occurred with a "familial MMR mutation (MSH6)" (Jori_2015), while an additional co-occurrence with a pathogenic variant has been reported via internal testing (MSH2 c.1786_1788delAAT, p.Asn596del), providing supporting evidence for a benign role. Experimental evidence concluded the variant to be neutral (e.g. Damaso_2020, Jia_2021, Scott_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 18033691, 19669161, 30306255, 34371384, 37262986, 24953332, 35245693, 34127009, 32635641, 35263119, 10978353, 33471991, 34204722, 10573010, 32957588, 26951660, 28202063, 33357406, 22703879, 26517685, 16614121, 31422574, 15849733, 25503501, 36243179, 27600092, 29212164, 31512090, 22949387, 31159747, 8993976, 16203774, 26580448, 36550560). ClinVar contains an entry for this variant (Variation ID: 41646). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000659882	SCV001135744	likely benign	Lynch syndrome 1	2024-04-09	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000076286	SCV001450729	likely benign	Lynch syndrome	2020-12-02	criteria provided, single submitter	clinical testing	The MSH2 c.1787A>G (p.Asn596Ser) missense change has a maximum subpopulation frequency of 0.054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47702191-A-G). This variant results in a conservative amino acid change and five of seven in silico tools predict a benign effect of this variant on protein function (BP4). To our knowledge, functional assays have not been performed. The variant has been identified in individuals with colorectal cancer or meeting Bethesda criteria of hereditary non-polyposis colorectal cancer (HPNCC; PMID: 18033691, 29212164, 16203774, 15849733), as well as individuals with unrelated phenotypes and no evidence of HPNCC (PMID: 22703879, 25637381, internal data). A family with this variant suggests lack of segregation since one of the affected family members did not carry the variant (BS4_Supporting; PMID: 10573010). Another report indicates that the variant co-occurred with a familial pathogenic MSH6 variant in one individual (BP2; PMID: 26517685). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS4_Supporting, BP2, BP4.
Genetic Services Laboratory, University of Chicago	RCV000200985	SCV002070922	likely benign	not specified	2018-10-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115511	SCV002534411	likely benign	Hereditary cancer-predisposing syndrome	2021-04-29	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149607	SCV003838306	likely benign	Breast and/or ovarian cancer	2023-05-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200985	SCV004243563	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115511	SCV005415562	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-10	criteria provided, single submitter	clinical testing	The missense variant NM_000251.3(MSH2):c.1787A>G (p.Asn596Ser) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn596Ser variant is observed in 19/34,586 (0.0549%) alleles from individuals of gnomAD Latino background in gnomAD, which is greater than expected for the disorder. There is a small physicochemical difference between asparagine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The serine residue at codon 596 of MSH2 is only present in a single other mammalian species: Lesser Egyptian jerboa. The nucleotide c.1787 in MSH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034554	SCV000043344	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	RCV000148641	SCV000190356	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034554	SCV001550511	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Asn596Ser variant was identified in 6 of 6092 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, breast cancer, and ovarian cancer and was not identified in 2712 control chromosomes from healthy individuals (Barnetson 2008, Genuardi 1999, Jalkh 2017, Pal 2012, Viel 1997, Woods 2005). The variant was also identified in the following databases: dbSNP (ID: rs41295288) as "With Uncertain significance allele", ClinVar (3x uncertain significance, including review by expert panel InSiGHT, 1x likely benign, 2x benign), Clinvitae, UMD-LSDB (2x, unclassified variant), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (12x, uncertain significance). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 82 of 277212 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 7 of 24034 chromosomes (freq: 0.0003), Other in 7 of 6464 chromosomes (freq: 0.001), Latino in 18 of 34416 chromosomes (freq: 0.0005), European in 43 of 126708 chromosomes (freq: 0.0003), Ashkenazi Jewish in 3 of 10152 chromosomes (freq: 0.0003), and South Asian in 4 of 30780 chromosomes (freq: 0.0001). The variant was not observed in the East Asian or Finnish populations. Two studies have identified this variant in a proband from a family with affected family members (father and two paternal first cousins who carried this variant), but it was not present in another paternal first cousin who was diagnosed with CRC and endometrial cancer at 46 and 48 respectively (Genuardi 1999, Viel 1997). The p.Asn596 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034554	SCV001740569	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034554	SCV001807063	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000034554	SCV001905904	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034554	SCV001953986	likely benign	not provided		no assertion criteria provided	clinical testing