2-47478481-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The ENST00000233146.7(MSH2):ā€‹c.2420C>Gā€‹(p.Thr807Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,806 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T807A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

MSH2
ENST00000233146.7 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.18
Variant links:
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 -1 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 15 uncertain in ENST00000233146.7
BP4
Computational evidence support a benign effect (MetaRNN=0.083931774).
BP6
Variant 2-47478481-C-G is Benign according to our data. Variant chr2-47478481-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.2420C>G p.Thr807Ser missense_variant 14/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.2420C>G p.Thr807Ser missense_variant 14/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461806
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2023This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 807 of the MSH2 protein (p.Thr807Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 18033691, 27601186). ClinVar contains an entry for this variant (Variation ID: 90968). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 01, 2023This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
17
DANN
Benign
0.22
DEOGEN2
Benign
0.34
T;.;.;.
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.37
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
T;T;T;T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.084
T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
-0.79
N;.;.;.
MutationTaster
Benign
0.62
N;N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
0.44
N;N;.;N
REVEL
Uncertain
0.34
Sift
Benign
1.0
T;T;.;T
Sift4G
Benign
1.0
T;T;.;T
Polyphen
0.0030
B;.;.;B
Vest4
0.32
MutPred
0.16
Loss of catalytic residue at T807 (P = 0.0716);.;Loss of catalytic residue at T807 (P = 0.0716);Loss of catalytic residue at T807 (P = 0.0716);
MVP
0.88
MPC
0.0068
ClinPred
0.34
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.15
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41295294; hg19: chr2-47705620; API