2-47403305-C-G
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_000251.3(MSH2):āc.114C>Gā(p.Asp38Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,603,832 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).
Frequency
Genomes: š 0.000072 ( 0 hom., cov: 33)
Exomes š: 0.0000062 ( 0 hom. )
Consequence
MSH2
NM_000251.3 missense
NM_000251.3 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 1.20
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.3824746).
BP6
Variant 2-47403305-C-G is Benign according to our data. Variant chr2-47403305-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90555.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=5}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000722 AC: 11AN: 152266Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000176 AC: 4AN: 226928Hom.: 0 AF XY: 0.0000162 AC XY: 2AN XY: 123628
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GnomAD4 exome AF: 0.00000620 AC: 9AN: 1451566Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5AN XY: 721158
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GnomAD4 genome AF: 0.0000722 AC: 11AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Lynch syndrome 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 27, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 16, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 26, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 29, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2024 | The p.D38E variant (also known as c.114C>G), located in coding exon 1 of the MSH2 gene, results from a C to G substitution at nucleotide position 114. The aspartic acid at codon 38 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in two individuals meeting Bethesda criteria from German cohorts wherein both individuals also carried additional pathogenic mutations: one individual had a deletion of MSH2 exon 3-5 (Grabowski M, Genet. Test. 2005; 9(2):138-46), and the specific pathogenic mutation was not named for the other individual (Mangold E, Int. J. Cancer 2005 Sep; 116(5):692-702). This alteration has been reported in an individual with MSI-high proximal colon cancer diagnosed between age 51 and 60 (Urso E, Int J Colorectal Dis 2008 Aug; 23(8):801-6). This alteration has also been reported as a variant of uncertain significance in a cohort of 1260 individuals undergoing Lynch syndrome testing (Yurgelun MB et al, Gastroenterology 2015 Sep; 149(3):604-613.e20). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 18, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer or suspected Lynch syndrome, and co-occurred with an in-frame MSH2 deletion (phase unknown) in two siblings with normal tumor immunohistochemistry (Grabowski 2005, Mangold 2005, Urso 2008, Yurgelun 2015); This variant is associated with the following publications: (PMID: 31428572, 18446350, 25980754, 15849733, 26333163, 15943554) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 08, 2021 | Variant summary: MSH2 c.114C>G (p.Asp38Glu) results in a conservative amino acid change located in the DNA mismatch repair ATPase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 226928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.114C>G has been reported in the literature in individuals affected with Lynch Syndrome, pancreatic cancer and hematological malignancies (Mangold_2005, Grabowski_2005, Urso_2008, Yurgelun_2015, Zhu_2021, Singhal_2021). These data do not allow any conclusion about variant significance. One co-occurrence with another pathogenic variant has been reported (MSH2 Del exons 3-5, in-frame deletion), however no clinical information and/or phase of two variants were provided by authors to rule out deleterious effect of c.114C>G (Grabowski_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;N
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Benign
T;.;T
Polyphen
B;.;B
Vest4
MutPred
Gain of glycosylation at T33 (P = 0.2055);Gain of glycosylation at T33 (P = 0.2055);Gain of glycosylation at T33 (P = 0.2055);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at