Submissions for variant NM_000251.3(MSH2):c.1748A>G (p.Asn583Ser)

gnomAD frequency: 0.00014  dbSNP: rs201118107

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034553	SCV000149419	likely benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 23047549, 22703879, 12658575, 18383312, 26898890, 27153395, 27600092, 26333163, 27720647, 30998989, 31159747)
Ambry Genetics	RCV000115510	SCV000186283	likely benign	Hereditary cancer-predisposing syndrome	2018-05-01	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000076263	SCV000257654	uncertain significance	Lynch syndrome	2015-06-05	criteria provided, single submitter	clinical testing
Invitae	RCV001079601	SCV000262297	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034553	SCV000601439	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034553	SCV000806011	uncertain significance	not provided	2018-01-10	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115510	SCV000822047	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765667	SCV000897009	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	RCV000115510	SCV000910730	likely benign	Hereditary cancer-predisposing syndrome	2016-03-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034553	SCV001152281	likely benign	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115510	SCV002534403	likely benign	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265576	SCV002547929	likely benign	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1748A>G (p.Asn583Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, 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 9.9e-05 in 282270 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (9.9e-05 vs 0.00057), allowing no conclusion about variant significance. c.1748A>G has been reported in the literature in multiple individuals suspected of hereditary cancer (e.g. Tsaousis_2019, Li_2020, Maxwell_2016), however these reports do not provide unequivocal evidence for association of the variant with disease. The variant was found co-occuring with pathogenic MLH1 variants (c.589-1G>T; c.1852_1854delAAG [p.Lys618del]), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant is not associated with breast cancer. Two publications found that the variant was functionally neutral in a cell survival assay (Bouvet_2019, Jia_2021). Ten ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance and six as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492329	SCV004239275	likely benign	Breast and/or ovarian cancer	2023-06-29	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034553	SCV000043343	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	RCV000148636	SCV000190351	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354468	SCV001549093	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Asn583Ser variant was identified in 3 of 1836 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, colon cancer, and atherosclerosis (Caminsky 2016, Johnston 2012, Wagner 2003). The variant was also identified in dbSNP (ID: rs201118107) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx and 5 clinical laboratories; classified as likely benign by Ambry Genetics, Invitae), Clinvitae (classified as uncertain significance by ClinVar; classified as likely benign by Invitae), UMD-LSDB (3x as unclassified variant), and the Insight Hereditary Tumors Database. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant c.1852_1854delAAG (p.Lys618del), increasing the likelihood that the p.Asn583Ser variant does not have clinical significance. In addition, a study by Wagner 2003 found this variant co-occurring with the MLH1 likely pathogenic variant c.589-1G>T. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 28 of 276902 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 24012 chromosomes (freq: 0.0002), Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 4 of 34414 chromosomes (freq: 0.0001), European in 15 of 126460 chromosomes (freq: 0.0001), East Asian in 1 of 18862 chromosomes (freq: 0.0001), Finnish in 1 of 25788 chromosomes (freq: 0.00004), and South Asian in 1 of 30760 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish population. The p.Asn583 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 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. This information is not predictive enough to assume 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.