Submissions for variant NM_000251.3(MSH2):c.146A>T (p.Asp49Val)

gnomAD frequency: 0.00001  dbSNP: rs63750335

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160615	SCV000211212	uncertain significance	not provided	2023-04-06	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; Published functional study demonstrates loss of function in yeast-based mutator assay (Martinez and Kolodner, 2010); Observed in an individual with colorectal cancer (Papp et al., 2007); This variant is associated with the following publications: (PMID: 22290698, 26333163, 18822302, 21120944, 20176959, 17569143)
Ambry Genetics	RCV000221403	SCV000277722	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The p.D49V variant (also known as c.146A>T), located in coding exon 1 of the MSH2 gene, results from an A to T substitution at nucleotide position 146. The aspartic acid at codon 49 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been identified in a Hungarian individual diagnosed with colorectal cancer at age 53 (Papp J et al, World J. Gastroenterol. 2007 May; 13(19):2727-32). Yeast mutator assays testing for MMR defects have shown that this allele results in loss of function (Martinez SL and Kolodner RD. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5070-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000684812	SCV000548154	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 49 of the MSH2 protein (p.Asp49Val). This variant is present in population databases (rs63750335, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 17569143). ClinVar contains an entry for this variant (Variation ID: 90675). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. Experimental studies have shown that this missense change affects MSH2 function (PMID: 20176959). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000221403	SCV000684939	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 49 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant has defective DNA damage repair function in a yeast assay (PMID: 20176959). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer (PMID: 17569143) and an individual affected with prostate cancer (PMID: 32268276). This variant has been identified in 2/231720 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.
Counsyl	RCV000662586	SCV000785212	uncertain significance	Lynch syndrome 1	2017-06-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267841	SCV002552184	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160615	SCV002585787	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	MSH2: PS3:Supporting, BP1
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000662586	SCV002762820	uncertain significance	Lynch syndrome 1	2022-12-09	criteria provided, single submitter	research	PS3_MOD, PS4_SUP, PM2_SUP
Myriad Genetics, Inc.	RCV000662586	SCV004018392	uncertain significance	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662586	SCV004194531	uncertain significance	Lynch syndrome 1	2023-06-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997148	SCV004828992	uncertain significance	Lynch syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 49 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant has defective DNA damage repair function in a yeast assay (PMID: 20176959). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer (PMID: 17569143) and an individual affected with prostate cancer (PMID: 32268276). This variant has been identified in 2/231720 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.