Submissions for variant NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn)

gnomAD frequency: 0.00002  dbSNP: rs763100088

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222363	SCV000278504	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The p.I648N variant (also known as c.1943T>A), located in coding exon 12 of the MSH2 gene, results from a T to A substitution at nucleotide position 1943. The isoleucine at codon 648 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been identified in identified in 1/369 Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). This alteration has also been reported in a MSI-H colorectal cancer with equivocal loss of the MSH6 protein (Poynter JN et al. Cancer Epidemiol Biomarkers Prev, 2008 Nov;17:3208-15). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000523371	SCV000618299	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27720647, 27601186, 24728327, 18822302, 21120944, 33357406, 18990764)
Invitae	RCV000629936	SCV000750892	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222363	SCV001736417	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with asparagine at codon 648 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 18990764, 27601186). This variant has been identified in 5/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523371	SCV002046202	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals and families with colorectal cancer (PMID: 18990764 (2008)), Lynch syndrome (PMID: 27601186 (2016)), and breast cancer (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). The frequency of this variant in the general population, 0.000044 (5/113734 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003469093	SCV004194552	uncertain significance	Lynch syndrome 1	2023-06-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998593	SCV004825050	uncertain significance	Lynch syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with asparagine at codon 648 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 18990764, 27601186). This variant has been identified in 5/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355204	SCV001550021	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Ile648Asn variant was identified in 1 of 738 proband chromosomes (frequency: 0.001) from individuals or families with lynch syndrome (Lagerstedt-Robinson 2016). The variant was also identified in dbSNP (ID: rs763100088) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, and Invitae), and Insight Hereditary Tumors Database (1x). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 5 of 246228 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111692 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Although the p.Ile648 residue is not conserved in mammals and other organisms, 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.