chr2-47478461-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_000251.3(MSH2):āc.2400A>Gā(p.Leu800=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L800L) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2400A>G | p.Leu800= | synonymous_variant | 14/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2400A>G | p.Leu800= | synonymous_variant | 14/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152214Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251420Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135882
GnomAD4 exome AF: 0.000129 AC: 188AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 92AN XY: 727206
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152214Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Oct 31, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 22, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Jun 28, 2017 | - - |
not provided Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 27, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | MSH2: BP4, BP7 - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 02, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 27, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 10, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2014 | 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. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2014 | 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. - |
MSH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 14, 2019 | 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). - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Leu800= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs201298777) as "With other allele ", ClinVar (classified as benign by GeneDx; as likely benign by Ambry Genetics, Invitae, Counsyl, and Color; and as uncertain significance by three submitters), and in UMD-LSDB (1x as neutral). The variant was identified in control databases in 14 of 277180 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 14 of 126676 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu800= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at