Submissions for variant NM_000251.3(MSH2):c.2164G>A (p.Val722Ile)

gnomAD frequency: 0.00001  dbSNP: rs587781996

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130409	SCV000185271	likely benign	Hereditary cancer-predisposing syndrome	2020-06-25	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.
Invitae	RCV000168465	SCV000219164	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000487305	SCV000565993	likely benign	not specified	2018-03-09	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.
Color Diagnostics, LLC DBA Color Health	RCV000130409	SCV000910890	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 722 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). Functional studies have shown that this variant does not affect mismatch DNA repair activity of MSH2 protein (PMID: 19697156, 21120944). In addition, this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in multiple individuals affected with colorectal cancer (PMID: 19697156, 28466842), an individual affected with breast or gynecological cancer (PMID: 29371908), and in a cohort of Swedish Lynch syndrome families (PMID: 27601186). In a large breast cancer case-control study, this variant was reported in 8 affected individuals and 16 unaffected controls (PMID: 33471991). This variant has also been observed in individuals unaffected with Lynch syndrome associated tumors (Color internal data). This variant has been identified in 16/282864 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000487305	SCV001432024	uncertain significance	not specified	2020-08-25	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2164G>A (p.Val722Ile) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251484 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00057), allowing no conclusion about variant significance. c.2164G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Christensen_2009, Haraldsdottir_2017, Lagerstedt-Robinson_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.1929delG, p.Arg645Glufs), providing supporting evidence for a benign role (Dominguez-Valentin_2018). In in vitro functional studies, the variant was found to have normal mismatch repair (MMR) activity similar to wild type (Christensen_2009). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000487305	SCV002068813	uncertain significance	not specified	2020-04-28	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2164G>A, in exon 13 that results in an amino acid change, p.Val722Ile. This sequence change has been described in the gnomAD database with a frequency of 0.011% in the European sub-population (dbSNP rs587781996). The p.Val722Ile change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. This sequence change appears to be deleterious based on in-silico pathogenicity prediction tools (PolyPhen, SIFT, Align GVGD). The p.Val722Ile change has been reported in patients with colorectal cancer (PMIDs: 19697156, 27601186); however, this sequence change was shown to behave similar to wild-type MSH2 in mismatch repair (MMR) activity and protein stability assays (PMID: 19697156). Due to these contrasting evidences, the clinical significance of the p.Val722Ile change remains unknown at this time.
Sema4, Sema4	RCV000130409	SCV002534455	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-26	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509191	SCV004220977	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 28466842 (2017), 27601186 (2016), 19697156 (2009)), breast cancer (PMIDs: 34326862 (2021), 30426508 (2018), 29371908 (2018)), and pancreatic cancer (PMID: 31673425 (2019)). A functional study indicated the variant does not affect MSH2 expression or DNA mismatch repair activity in vitro (PMID: 19697156 (2009)), however additional studies are needed to corroborate this finding. The frequency of this variant in the general population, 0.00011 (14/129180 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004532559	SCV004753826	likely benign	MSH2-related disorder	2019-11-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV003998056	SCV004825703	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 722 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). Functional studies have shown that this variant does not affect mismatch DNA repair activity of MSH2 protein (PMID: 19697156, 21120944). In addition, this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in multiple individuals affected with colorectal cancer (PMID: 19697156, 28466842), an individual affected with breast or gynecological cancer (PMID: 29371908), and in a cohort of Swedish Lynch syndrome families (PMID: 27601186). In a large breast cancer case-control study, this variant was reported in 8 affected individuals and 16 unaffected controls (PMID: 33471991). This variant has also been observed in individuals unaffected with Lynch syndrome associated tumors (Color internal data). This variant has been identified in 16/282864 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.
GenomeConnect, ClinGen	RCV000509191	SCV000607173	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.