Submissions for variant NM_000251.3(MSH2):c.382C>G (p.Leu128Val)

gnomAD frequency: 0.00006  dbSNP: rs145649774

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719858	SCV000149437	likely benign	not provided	2019-04-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27449771, 23047549, 23729658, 25479140)
Ambry Genetics	RCV000115528	SCV000187641	likely benign	Hereditary cancer-predisposing syndrome	2019-03-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000524406	SCV000254420	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212583	SCV000604261	uncertain significance	not specified	2016-11-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212583	SCV000696263	likely benign	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.382C>G (p.Leu128Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 121402 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the ExAC database. The observed variant frequency within South Asian control individuals in the ExAC database is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.382C>G has been reported in the literature in individuals affected with a variety of cancers such as ovarian, pancreatic, breast, prostate (example, Pal_2012, Grant_2015, Amemiya_2015, Yang_2016). In one family with this variant, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Juhari_2018). These data suggest the variant of interest does not co-segregate with the disease. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and conflicting assessments (VUS, n=5, likely benign, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000195415	SCV000837818	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115528	SCV000910713	likely benign	Hereditary cancer-predisposing syndrome	2017-06-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000986649	SCV001135700	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986649	SCV001304223	uncertain significance	Lynch syndrome 1	2018-09-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719858	SCV002046560	likely benign	not provided	2023-09-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001719858	SCV003808954	uncertain significance	not provided	2022-04-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492474	SCV004239286	likely benign	Breast and/or ovarian cancer	2023-03-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353804	SCV000592463	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH2, p.Leu128Val variant was not identified in the literature. The p.Leu128Val variant was identified in dbSNP (ID: rs145649774) as “With Uncertain significance allele”, Clinvitae database (classified as VUS), MUTDB, ClinVar database (classified as uncertain significance, submitters: GeneDx, Ambry Genetics, Invitae), and UMD (1x with an “unclassified variant” classification).The p.Leu128Val variant was also identified in the NHLBI GO Exome Sequencing Project in 3 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 30 of 16512 chromosomes (frequency: 0.002) of South Asian individuals, 9 of 66732 (frequency: 0.00013) of European (Non-Finnish) individuals, 1 of 10404 (frequency: 9.61E-05) of African individuals, 1 of 11578 (frequency: 8.64E-05) of Latino individuals and 2 of 908 (frequency: 0.002) in other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Leu128 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Leu128Val variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time but we would lean towards a more benign role for this variant. This variant is classified as likely benign.
GenomeConnect, ClinGen	RCV000195415	SCV000607332	not provided	Lynch syndrome		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.
True Health Diagnostics	RCV000115528	SCV000788038	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-11	no assertion criteria provided	clinical testing