Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000251.3(MSH2):c.317G>A(p.Arg106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,611,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R106T) has been classified as Uncertain significance.
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.046949625).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-47408506-G-A is Benign according to our data. Variant chr2-47408506-G-A is described in ClinVar as [Benign]. Clinvar id is 91062.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47408506-G-A is described in Lovd as [Likely_benign]. Variant chr2-47408506-G-A is described in Lovd as [Benign].
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
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Uncertain significance, no assertion criteria provided
research
Mayo Clinic Laboratories, Mayo Clinic
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Likely benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
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not provided Benign:3
Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
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Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Mar 11, 2021
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Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Nov 26, 2019
This variant is associated with the following publications: (PMID: 22949387, 22290698, 18033691, 16736289) -
Lynch syndrome 1 Benign:2
Benign, criteria provided, single submitter
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Sep 21, 2015
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Benign, criteria provided, single submitter
clinical testing
Pathway Genomics
Oct 30, 2014
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Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Oct 03, 2016
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Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 10, 2015
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. -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Sep 12, 2022
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Lynch syndrome Benign:1
Benign, reviewed by expert panel
research
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Sep 05, 2013
Multifactorial likelihood analysis posterior probability <0.001 -