chr2-47799169-C-G
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_000179.3(MSH6):c.1186C>G(p.Leu396Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,614,176 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L396F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1186C>G | p.Leu396Val | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.1186C>G | p.Leu396Val | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00535 AC: 814AN: 152194Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00540 AC: 1355AN: 251120Hom.: 7 AF XY: 0.00530 AC XY: 719AN XY: 135750
GnomAD4 exome AF: 0.00681 AC: 9952AN: 1461864Hom.: 41 Cov.: 34 AF XY: 0.00659 AC XY: 4793AN XY: 727240
GnomAD4 genome ? AF: 0.00534 AC: 814AN: 152312Hom.: 3 Cov.: 32 AF XY: 0.00545 AC XY: 406AN XY: 74480
ClinVar
Submissions by phenotype
not specified Benign:9Other:1
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 23, 2018 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 15, 2017 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2013 | 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. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Lynch syndrome 5 Benign:6
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Oct 06, 2023 | BA1 based on allele frequency in NFE of 0.007213. - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Jul 11, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:5
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 27, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 20, 2014 | This alteration is classified as 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 01, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Dec 03, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 20, 2018 | - - |
Lynch syndrome Benign:3
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability <0.001 - |
Benign, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 17, 2015 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 06, 2021 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Leu396Val variant has been previously reported in about 9/5154 proband chromosomes in individuals with Lynch syndrome, sporadic colorectal cancer and endometrial cancer. It has also been observed in 3/5148 control chromosomes (Kim_2004_15340264, Kolodner_1999_10537275, Martinez_2010_20176959, Niessen_2006_16408224, Nilbert_2009_18566915, Perez-Cabornero_2009_19250818, Schafmayer_2007_17417778, Steinke_2008_18301448, Vahteristo_2005_15805151). It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs2020908) with an average heterozygosity score and standard error of 0.008+/-0.064, and a global minor allele frequency (MAF) of 0.004 (1000 Genomes), increasing the likelihood that this is a benign variant. The variant was also identified as a low frequency variant from HapMap samples of different populations of origin as well as in the EPS project as a low frequency variant increasing the liklihood this variant is benign. This residue is conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest this variant may impact protein function. However, this information is not very predictive of pathogenicity. Two functional Saccharomyces cerevisiae-based studies have shown that the MMR activity of the variant is comparable to the wild type protein (Kolodner_1999_10537275, Martinez_2010_20176959), increasing the likelihood that the p.Leu396Val variant is not clinically significant. In summary, based on the above information, this variant is classified as Benign. - |
Lynch syndrome 1 Benign:1
Benign, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MSH6: BP4, BS2 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at